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CAR T-CELL THERAPY MARKET: 2020 – 2027

G L O B A L  M A R K E T  A N A L Y S I S  A N D

I N D U S T R Y  F O R E C A S T

 

DISCLAIMER

LPBI Group’s decision to publish the Table of Contents of this Report does not imply endorsement of the Report

Aviva Lev-Ari, PhD, RN, Founder 1.0 & 2.0 LPBI Group

Guest Reporter: MIKE WOOD

Marketing Executive
BIOTECH FORECASTS

 

ABOUT BIOTECH FORECASTS

BIOTECH FORECASTS is a full-service market research and business- consulting firm primarily focusing on healthcare, pharmaceutical, and biotechnology industries. BIOTECH FORECASTS provides global as well as medium and small Pharmaceutical and Biotechnology businesses with unmatched quality of “Market Research Reports” and “Business Intelligence Solutions”. BIOTECH FORECASTS has a targeted view to provide business insights and consulting to assist its clients to make strategic business decisions, and achieve sustainable growth in their respective market domain.

UPDATED on 10/13/2020

CAR T-CELL THERAPY MARKET

Mike Wood

Mike Wood

Marketing Executive at Biotech Forecasts

CAR T-cell therapy as a part of adoptive cell therapy (ACT), has become one of the most rapidly growing and promising fields in the Immuno-oncology. As compared to the conventional cancer therapies, CAR T-cell therapy is the single-dose solution for the treatment of various cancers, significantly for some lethal forms of hematological malignancies.

CAR T-cell therapy mainly involves the use of engineered T-cells, the process starts with the extraction of T-cells through leukapheresis, either from the patient (autologous) or a healthy donor (allogeneic). After the expression of a synthetic receptor (Chimeric Antigen Receptor) in the lab, the altered T-cells are expanded to the right dose and administered into the patient’s body. where they target and attach to a specific antigen on the tumor surface, to kill the cancerous cells by igniting the apoptosis.

The global CAR T-cell therapy market was valued at $734 million in 2019 and is estimated to reach $4,078 million by 2027, registering a CAGR of 23.91% from 2020 to 2027.

Factors that drive the market growth involve, (1) Increased in funding for R&D activities pertaining to cell and gene therapy. By H1 2020 cell and gene therapy companies set new records in the fundraising despite the pandemic crisis. For Instance, by June 2020 totaled $1,452 Million raised in Five IPOs including, Legend Biotech ($487M), Passage Bio ($284M), Akouos ($244M), Generation Bio ($230M), and Beam Therapeutics ($207M), which is 2.5 times the total IPO of 2019.

Moreover, in 2019 cell therapy companies specifically have raised $560 million of venture capital, including Century Therapeutics ($250M), Achilles Therapeutics Ltd. ($121M in series B), NKarta Therapeutics Inc. ($114M), and Tmunity Therapeutics ($75M in Series B).

(2) Increased in No. of Approved Products, By July 2020, there are a total of 03 approved CAR T-cell therapy products, including KYMRIAH®, YESCARTA®, and the most recently approved TECARTUS™ (formerly KTE-X19). Furthermore, two CAR T-cell therapies BB2121, and JCAR017 are expected to get the market approval by the end of 2020 or in early 2021.

Other factors that boost the market growth involves; (3) increase in government support, (4) ethical acceptance of Cell and Gene therapy for cancer treatment, (5) rise in the prevalence of cancer, and (6) an increase in awareness regarding the CAR T-cell therapy.

However, high costs associated with the treatment (KYMRIAH® cost around $475,000, and YESCARTA® costs $373,000 per infusion), long production hours, obstacles in treating solid tumors, and unwanted immune responses & potential side effects might hamper the market growth.

The report also presents a detailed quantitative analysis of the current market trends and future estimations from 2020 to 2027.

The forecasts cover 2 Approach Types, 5 Antigen Types, 5 Application Types, Regions, and 14 Countries.

The report comes with an associated file covering quantitative data from all numeric forecasts presented in the report, as well as with a Clinical Trials Data File.

KEY FINDINGS

The report has the following key findings:

  • The global CAR T-cell therapy market accounted for $734 million in 2019 and is estimated to reach $4,078 million by 2027, registering a CAGR of 23.91% from 2020 to 2027.
  • By approach type the autologous segment was valued at $655.26 million in 2019 and is estimated to reach $ 3,324.52 million by 2027, registering a CAGR of 22.51% from 2020 to 2027.
  • By approach type, the allogeneic segment exhibits the highest CAGR of 32.63%.
  • Based on the Antigen segment CD19 was the largest contributor among the other segments in 2019.
  • The Acute lymphocytic leukemia (ALL) segment generated the highest revenue and is expected to continue its dominance in the future, followed by the Diffuse large B-cell lymphoma (DLBCL) segment.
  • North America dominated the global CAR T-cell therapy market in 2019 and is projected to continue its dominance in the future.
  • China is expected to grow the highest in the Asia-Pacific region during the forecast period.

TOPICS COVERED

The report covers the following topics:

  • Market Drivers, Restraints, and Opportunities
  • Porters Five Forces Analysis
  • CAR T-Cell Structure, Generations, Manufacturing, and Pricing Models
  • Top Winning Strategies, Top Investment Pockets
  • Analysis of by Approach Type, Antigen Type, Application, and Region
  • 51 Company Profiles, Product Portfolio, and Key Strategies
  • Approved Products Profiles, and list of Expected Approvals
  • COVID-19 Impact on the Cell and Gene Therapy Industry
  • CAR T-cell therapy clinical trials analysis from 1997 to 2019
  • Market analysis and forecasts from 2020 to 2027

FORECAST SEGMENTATION

By Approach Type

  • Autologous
  • Allogeneic

By Antigen Type

  • CD19
  • CD20
  • BCMA
  • MSLN
  • Others

By Application

  • Acute lymphoblastic leukemia (ALL)
  • Diffuse large B-Cell lymphoma (DLBCL)
  • Multiple Myeloma (MM)
  • Acute Myeloid Leukemia (AML)
  • Other Cancer Indications

By Region

  • North America: USA, Canada, Mexico
  • Europe: UK, Germany, France, Spain, Italy, Rest of Europe
  • Asia-Pacific: China, Japan, India, South Korea, Rest of Asia-Pacific
  • LAMEA: Brazil, South Africa, Rest of LAMEA

Contact at info@biotechforecasts.com for any Queries or Free Report Sample

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Published by

Mike Wood
Marketing Executive at Biotech Forecasts
1 article
The global CAR T-cell therapy market was valued at $734 million in 2019 and is estimated to reach $4,078 million by 2027, registering a CAGR of 23.91% from 2020 to 2027. hashtagcelltherapy hashtaggenetherapy hashtagimmunotherapy hashtagcancertreatment hashtagcartcell hashtagregenerativemedicine hashtagbiotech hashtagcancer

 

Table of Contents

 

CHAPTER 1: INTRODUCTION

1.1 REPORT DESCRIPTION 17
1.2 TOPICS COVERED 19
1.3 KEY MARKET SEGMENTS 20
1.4 KEY BENEFITS 21
1.5 RESEARCH METHODOLOGY 21
1.6 TARGET AUDIENCE 22
1.7 COMPANIES MENTIONED 23

CHAPTER 2: EXECUTIVE SUMMARY

2.1 EXECUTIVE SUMMARY 26
2.2 CXO PROSPECTIVE 29

CHAPTER 3: MARKET OVERVIEW

3.1 MARKET DEFINITION AND SCOPE 30
3.2 KEY FINDINGS 31
3.3 TOP INVESTMENT POCKETS 32
3.4 TOP WINNING STRATEGIES 33
3.4.1.Top winning strategies, by year, 2017-2019* 34
3.4.2.Top winning strategies, by development, 2017-2019*(%) 34
3.4.3.Top winning strategies, by company, 2017-2019* 35
3.5 TOP PLAYER POSITIONING, BY PIPELINE VOLUME, 2019 38
3.6 PORTERS FIVE FORCES ANALYSIS 39
3.7 COVID19 IMPACT ON CELL AND GENE THERAPY (CGT) INDUSTRY 41
3.8 MARKET DYNAMICS 46
3.8.1    Drivers 46
3.8.1.1   Increase in funding for R&D activities of CAR T-cell therapy 46
3.8.1.2   The rise in the prevalence of cancer 47
3.8.1.3   Increase in awareness regarding CAR T-cell therapy 47

 

3.8.2    Restrains 48
3.8.2.1   The high cost of CAR T-cell therapy treatment 48
3.8.2.2   Unwanted immune responses and side effects 48
3.8.2.3   Long production time 48
3.8.2.4   Obstacles in treating solid tumors 49
3.8.3    Opportunities 49
3.8.3.1   Untapped potential for emerging markets 49

CHAPTER 4: CAR T-CELL THERAPY, A BRIEF INTRODUCTION

4.1 OVERVIEW 50
4.2 SIXTY YEARS HISTORY OF CAR T-CELL THERAPY 51
4.3 CAR T-CELL STRUCTURE AND GENERATIONS 53
4.4 CAR T-CELL MANUFACTURING PROCESSES 56
4.5 PRICING AND PAYMENT MODELS FOR CAR T-CELL THERAPIES 59

CHAPTER 5: CAR T-CELL THERAPY MARKET, BY APPROACH TYPE

5.1 OVERVIEW 61
5.1.1    Market size and forecast 62
5.2 AUTOLOGOUS 63
5.2.1    Key market trends 63
5.2.2    Key growth factors and opportunities 64
5.2.3    Market size and forecast 64
5.2.4    Market size and forecast by country 65
5.3 ALLOGENEIC 66
5.3.1    Key market trends 67
5.3.2    Key growth factors and opportunities 68
5.3.3    Market size and forecast 68
5.3.4    Market size and forecast by country 69

CHAPTER 6: CAR T-CELL THERAPY MARKET, BY ANTIGEN TYPE

6.1 OVERVIEW 70
6.1.1         Market size and forecast 71
6.2 CD19 72
6.2.1         Market size and forecast 73
6.2.2         Market size and forecast by country 74

 

6.3 CD20 75
6.3.1 Market size and forecast 76
6.3.2 Market size and forecast by country 77
6.4 BCMA 78
6.4.1 Market size and forecast 79
6.4.2 Market size and forecast by country 80
6.5 MSLN 81
6.5.1 Market size and forecast 82
6.5.2 Market size and forecast by country 83
6.6 OTHERS 84
6.6.1 Market size and forecast 85
6.6.2 Market size and forecast by country 86

CHAPTER 7: CAR T-CELL THERAPY MARKET, BY APPLICATION

7.1 OVERVIEW 87
7.1.1       Market size and forecast 88
7.2 ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) 89
7.2.1       Market size and forecast 90
7.2.2       Market size and forecast by country 91
7.3 DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) 92
7.3.1       Market size and forecast 93
7.3.2       Market size and forecast by country 94
7.4 MULTIPLE MYELOMA (MM) 95
7.4.1       Market size and forecast 96
7.4.2       Market size and forecast by country 97
7.5 ACUTE MYELOID LEUKEMIA (AML) 98
7.5.1       Market size and forecast 99
7.5.2       Market size and forecast by country 100
7.6 OTHERS 101
7.6.1       Market size and forecast 102
7.6.2       Market size and forecast by country 103

CHAPTER 8: CAR T-CELL THERAPY MARKET, BY REGION

8.1 OVERVIEW 104
8.1.1       Market size and forecast 104
8.2 NORTH AMERICA 105
8.2.1       Key market trends 105
8.2.2       Key growth factors and opportunities 105

 

8.2.3       Market size and forecast, by country 106
8.2.4       Market size and forecast, by approach type 106
8.2.5       Market size and forecast, by antigen type 107
8.2.6 Market size and forecast, by application 107
8.2.6.1 U.S. market size and forecast, by approach type 108
8.2.6.2 U.S. market size and forecast, by antigen type 108
8.2.6.3 U.S. market size and forecast, by application 109
8.2.6.4 Canada market size and forecast, by approach type 110
8.2.6.5 Canada market size and forecast, by antigen type 110
8.2.6.6 Canada market size and forecast, by application 111
8.2.6.7 Mexico market size and forecast, by approach type 112
8.2.6.8 Mexico market size and forecast, by antigen type 112
8.2.6.9 Mexico market size and forecast, by application 113
8.3 EUROPE 114
8.4.1 Key market trends 114
8.4.2 Key growth factors and opportunities 114
8.4.3 Market size and forecast, by country 115
8.4.4 Market size and forecast, by approach type 115
8.4.5 Market size and forecast, by antigen type 116
8.4.6 Market size and forecast, by application 116
8.3.6.1 UK market size and forecast, by approach type 117
8.3.6.2 UK market size and forecast, by antigen type 117
8.3.6.3 UK market size and forecast, by application 118
8.3.6.4 Germany market size and forecast, by approach type 119
8.3.6.5 Germany market size and forecast, by antigen type 119
8.3.6.6 Germany market size and forecast, by application 120
8.3.6.7 France market size and forecast, by approach type 121
8.3.6.8 France market size and forecast, by antigen type 121
8.3.6.9 France market size and forecast, by application 122
8.3.6.10 Spain market size and forecast, by approach type 123
8.3.6.11 Spain market size and forecast, by antigen type 123
8.3.6.12 Spain market size and forecast, by application 124
8.3.6.13 Italy market size and forecast, by approach type 125
8.3.6.14 Italy market size and forecast, by antigen type 125
8.3.6.15 Italy market size and forecast, by application 126
8.3.6.16 Rest of Europe market size and forecast, by approach type 127
8.3.6.17 Rest of Europe market size and forecast, by antigen type 127
8.3.6.18 Rest of Europe market size and forecast, by application 128
8.4 ASIA-PACIFIC 129
8.4.1 Key market trends 129
8.4.2 Key growth factors and opportunities 129
8.4.3 Market size and forecast, by country 130
8.4.4 Market size and forecast, by approach type 130

 

8.4.5       Market size and forecast, by antigen type 131
8.4.6 Market size and forecast, by application 131
8.4.6.1 China market size and forecast, by approach type 132
8.4.6.2 China market size and forecast, by antigen type 132
8.4.6.3 China market size and forecast, by application 133
8.4.6.4 Japan market size and forecast, by approach type 134
8.4.6.5 Japan market size and forecast by antigen type 134
8.4.6.6 Japan market size and forecast, by application 135
8.4.6.7 India market size and forecast, by approach type 136
8.4.6.8 India market size and forecast, by antigen type 136
8.4.6.9 India market size and forecast, by application 137
8.4.6.10 South Korea market size and forecast, by approach type 138
8.4.6.11 South Korea market size and forecast, by antigen type 138
8.4.6.12 South Korea market size and forecast, by application 139
8.4.6.13 Rest of Asia-Pacific market size and forecast, by approach type 140
8.4.6.14 Rest of Asia-Pacific market size and forecast, by antigen type 140
8.4.6.15 Rest of Asia-Pacific market size and forecast, by application 141
8.5 LAMEA 142
8.5.1 Key market trends 142
8.5.2 Key growth factors and opportunities 142
8.5.3 Market size and forecast, by country 143
8.5.4 Market size and forecast, by approach type 143
8.5.5 Market size and forecast, by antigen type 144
8.5.6 Market size and forecast, by application 144
8.5.6.1 Brazil market size and forecast by approach type 145
8.5.6.2 Brazil market size and forecast, by antigen type 145
8.5.6.3 Brazil market size and forecast, by application 146
8.5.6.4 South Africa market size and forecast, by approach type 147
8.5.6.5 South Africa market size and forecast, by antigen type 147
8.5.6.6 South Africa market size and forecast, by application 148
8.5.6.7 Rest of LAMEA market size and forecast by approach type 149
8.5.6.8 Rest of LAMEA market size and forecast, by antigen type 149
8.5.6.9 Rest of LAMEA market size and forecast, by application 150

CHAPTER 9: CLINICAL TRIALS ANALYSIS & PRODUCT PROFILES

9.1 OVERVIEW 151
9.1.1      No. of Clinical Trials from 1997 to 2019 151
9.1.2      Clinical Trials from 1997 to 2019: Based on Approach Type 152
9.1.3      Clinical Trials from 1997 to 2019: Based on Antigen Type 153
9.1.4      Clinical Trials from 1997 to 2019: Based on Application 154
9.1.5      Clinical Trials from 1997 to 2019: Based on Region 155

 

9.2 EXPECTED APPROVALS 156
9.3 APPROVED PRODUCTS PROFILES 157
9.3.1      KYMRIAH® 157
9.3.2      YESCARTA® 159
9.3.3      TECARTUS™ 161

CHAPTER 10: COMPANY PROFILES

10.1       Abbvie Inc. 162
10.2       Adaptimmune Therapeutics Plc 164
10.3 Allogene Therapeutics, Inc. 166
10.4 Amgen, Inc 168
10.5 Anixa Biosciences, Inc. 170
10.6 Arcellx, Inc. 172
10.7 Atara Biotherapeutics, Inc. 173
10.8 Autolus Therapeutics Plc. 175
10.9 Beam Therapeutics, Inc. 177
10.10 Bellicum Pharmaceuticals, Inc. 179
10.11 BioNtech SE 181
10.12 Bluebird Bio, Inc. 183
10.13 Carsgen Therapeutics, Ltd 185
10.14 Cartesian Therapeutics, Inc. 187
10.15 Cartherics Pty Ltd. 188
10.16 Celgene Corporation 189
10.17 Cellectis SA 191
10.18 Cellular Biomedicine Group, Inc. 193
10.19 Celularity, Inc. 195
10.20 Celyad SA 196
10.21 CRISPR Therapeutics AG 198
10.22 Eureka Therapeutics, Inc. 200
10.23 Fate Therapeutics, Inc. 201
10.24 Fortress Biotech, Inc 203
10.25 Gilead Sciences, Inc. 205
10.26 Gracell Biotechnology Ltd 207
10.27 icell Gene Therapeutics 208
10.28 Johnson & Johnson 209
10.29 Juventas Cell Therapy Ltd. 211
10.30 Kuur Therapeutics 212
10.31 Legend Biotech Corp. 213
10.32 Leucid Bio Ltd. 214
10.33 Minerva Biotechnologies Corp. 215

 

10.34     Molecular Medicine SPA (Molmed) 216
10.35     Nanjing Bioheng Biotech Co., Ltd. 218
10.36     Noile-Immune Biotech Inc. 219
10.37     Novartis AG 220
10.38     Oxford Biomedica PLC 222
10.39     Persongen Biotherapeutics (Suzhou) Co., Ltd. 224
10.40     Poseida Therapeutics, Inc. 226
10.41     Precigen, Inc. 227
10.42     Precision Biosciences, Inc. 229
10.43     Sorrento Therapeutics, Inc. 231
10.44     Takara Bio Inc. 233
10.45     Takeda Pharmaceutical Company Ltd. 235
10.46     TC Biopharm Ltd. 237
10.47     Tessa Therapeutics Pte Ltd. 238
10.48     Tmunity Therapeutics, Inc. 239
10.49     Unum Therapeutics Inc. 240
10.50     Xyphos Inc. 242
10.51     Ziopharm Oncology, Inc. 243

CHAPTER 11: CONCLUSION & STRATEGIC RECOMMENTATIONS

11.1     STRATEGIC RECOMMENDATIONS 245
11.2     CONCLUSION 247

 

CONTACT

info@biotechforecasts.com

MIKE WOOD

Marketing Executive

BIOTECH FORECASTS

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Reporter: Stephen J. Williams, PhD

New Drugs on the Horizon: Part 3
Introduction

Andrew J. Phillips, C4 Therapeutics

  • symposium brought by AACR CICR and had about 30 proposals for talks and chose three talks
  • unfortunately the networking event is not possible but hope to see you soon in good health

ABBV-184: A novel survivin specific T cell receptor/CD3 bispecific therapeutic that targets both solid tumor and hematological malignancies

Edward B Reilly
AbbVie Inc. @abbvie

  • T-cell receptors (TCR) can recognize the intracellular targets whereas antibodies only recognize the 25% of potential extracellular targets
  • survivin is expressed in multiple cancers and correlates with poor survival and prognosis
  • CD3 bispecific TCR to survivn (Ab to CD3 on T- cells and TCR to survivin on cancer cells presented in MHC Class A3)
  • ABBV184  effective in vivo in lung cancer models as single agent;
  • in humanized mouse tumor models CD3/survivin bispecific can recruit T cells into solid tumors; multiple immune cells CD4 and CD8 positive T cells were found to infiltrate into tumor
  • therapeutic window as measured by cytokine release assays in tumor vs. normal cells very wide (>25 fold)
  • ABBV184 does not bind platelets and has good in vivo safety profile
  • First- in human dose determination trial: used in vitro cancer cell assays to determine 1st human dose
  • looking at AML and lung cancer indications
  • phase 1 trial is underway for safety and efficacy and determine phase 2 dose
  • survivin has very few mutations so they are not worried about a changing epitope of their target TCR peptide of choice

The discovery of TNO155: A first in class SHP2 inhibitor

Matthew J. LaMarche
Novartis @Novartis

  • SHP2 is an intracellular phosphatase that is upstream of MEK ERK pathway; has an SH2 domain and PTP domain
  • knockdown of SHP2 inhibits tumor growth and colony formation in soft agar
  • 55 TKIs there are very little phosphatase inhibitors; difficult to target the active catalytic site; inhibitors can be oxidized at the active site; so they tried to target the two domains and developed an allosteric inhibitor at binding site where three domains come together and stabilize it
  • they produced a number of chemical scaffolds that would bind and stabilize this allosteric site
  • block the redox reaction by blocking the cysteine in the binding site
  • lead compound had phototoxicity; used SAR analysis to improve affinity and reduce phototox effects
  • was very difficult to balance efficacy, binding properties, and tox by adjusting stuctures
  • TNO155 is their lead into trials
  • SHP2 expressed in T cells and they find good combo with I/O with uptick of CD8 cells
  • TNO155 is very selective no SHP1 inhibition; SHP2 can autoinhibit itself when three domains come together and stabilize; no cross reactivity with other phosphatases
  • they screened 1.5 million compounds and got low hit rate so that is why they needed to chemically engineer and improve on the classes they found as near hits

Closing Remarks

 

Xiaojing Wang
Genentech, Inc. @genentech

Follow on Twitter at:

@pharma_BI

@AACR

@CureCancerNow

@pharmanews

@BiotechWorld

@HopkinsMedicine

#AACR20

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Drugging Undrugged Cancer Targets 1:30 pm – 5:00 pm

SESSION VMS.ET01.01 – Drugging Undrugged Cancer Targets

April 27, 2020, 1:30 PM – 3:30 PM
Virtual Meeting: All Session Times Are U.S. EDT

Session Type
Virtual Minisymposium
Track(s)
Experimental and Molecular Therapeutics,Drug Development
18 Presentations
1:30 PM – 1:30 PM
– ChairpersonPeter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA

1:30 PM – 1:30 PM
– ChairpersonJohn S. Lazo. University of Virginia, Charlottesville, VA

1:30 PM – 1:35 PM
– IntroductionPeter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA

1:35 PM – 1:45 PM
3398 – PTPN22 is a systemic target for augmenting antitumor immunityWon Jin Ho, Jianping Lin, Ludmila Danilova, Zaw Phyo, Soren Charmsaz, Aditya Mohan, Todd Armstrong, Ben H. Park, Elana J. Fertig, Zhong-Yin Zhang, Elizabeth M. Jaffee. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD, Purdue University, Baltimore, MD, Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD, Vanderbilt University Medical Center, Baltimore, MD

Abstract: Remarkable progress in cancer immunology has revolutionized cancer therapy. The majority of patients, however, do not respond to immunotherapeutic options, warranting the ongoing search for better strategies. Leveraging the established role of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in autoimmune diseases, we hypothesized that PTPN22 is a novel target for cancer immunotherapy. PTPN22 is a physiologic regulator of T cell receptor (TCR) signaling acting by dephosphorylating activating tyrosine residues in Lck and Zap70. We first confirmed the relevance of PTPN22 expression by exploring its expression in multiple human cancer types using The Cancer Genome Atlas (TCGA). PTPN22 expression positively correlated with T cell and M1 macrophage gene signatures and immune regulatory genes, especially inflamed tumor types. Next, we directly investigated the role of PTPN22 in antitumor immunity by comparing in vivo tumor characteristics in wild-type (WT) and PTPN22 knockout (KO) mice. Consistent with our hypothesis, PTPN22 KO mice resisted MC38 and EG7 tumors significantly compared with WT. Mass cytometry (CyTOF) profiling of the immune tumor microenvironment demonstrated that MC38 tumors in PTPN22 KO mice were infiltrated with greater numbers of T cells, particularly CD8+ T cells expressing granzyme B and PD1. To further delineate the effects of PTPN22 KO on TCR signaling, we established an optimized CyTOF panel of 9 phosphorylation sites involved in the TCR signaling pathway, including two enzymatic substrates of PTPN22 (Lck Y394 and Zap70 Y493) and 15 immune subtyping markers. CyTOF phospho-profiling of CD8 T cells from tumor-bearing mouse spleens and the peripheral blood of immunotherapy-naïve cancer patients showed that the phosphorylated state of Zap70 Y493 correlated strongly with granzyme B expression. Furthermore, phospho-profiling of tumor-infiltrating CD8+ T cells (a measure of T cell activation) revealed the highest TCR-pathway phosphorylation levels in memory CD8+ T cells that express PD1. The difference in phosphorylation levels between WT and PTPN22 KO was most pronounced for Lck Y394. Based on these findings, we then hypothesized that PD1 inhibition will further enhance the antitumor immune responses promoted by the lack of PTPN22. Indeed, PTPN22 KO mice bearing MC38 and EG7 tumors responded more significantly to anti-PD1 therapy when compared with tumor-bearing WT mice. Finally, we treated WT tumor bearing mice with two different small molecule inhibitors of PTPN22, one previously published compound, LTV1, and one novel compound, L1 (discovered through structure based synthesis). While both inhibitors phenocopied the PTPN22 KO mice in resisting MC38 tumor growth, L1 treatment gave an immune profile that resembled what was observed in tumor-bearing PTPN22 KO mice. Taken together, our results demonstrate that PTPN22 is a novel systemic target for augmenting antitumor immunity.

  • can they leverage autoimmune data to look at new targets for checkpoint inhibition; we have a long way to go in immunooncology as only less than 30-40% of cancer types respond
  • using Cancer Genome Atlas PTPN22 is associated with autoimmune disorders
  • PTPN22 KO increases many immune cells; macrophages t-cells and when KO in tumors get more t cell infiltrate
  • PTP KO enhances t cell response, and may be driving t cells to exhaustion
  • made a inhibitor or PTPN22; antitumor phenotype when given inhibitor was like KO mice; a PDL1 inhibitor worked in KO mice
  • PTPN22 only in select hematopoetic cells

1:45 PM – 1:50 PM
– Discussion

1:50 PM – 2:00 PM
3399 – Preclinical evaluation of eFT226, a potent and selective eIF4A inhibitor with anti-tumor activity in FGFR1,2 and HER2 driven cancers. Peggy A. Thompson, Nathan P. Young, Adina Gerson-Gurwitz, Boreth Eam, Vikas Goel, Craig R. Stumpf, Joan Chen, Gregory S. Parker, Sarah Fish, Maria Barrera, Eric Sung, Jocelyn Staunton, Gary G. Chiang, Kevin R. Webster. eFFECTOR Therapeutics, San Diego, CA @RuggeroDavide

Abstract: Mutations or amplifications affecting receptor tyrosine kinases (RTKs) activate the RAS/MAPK and PI3K/AKT signaling pathways thereby promoting cancer cell proliferation and survival. Oncoprotein expression is tightly controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex consisting of eIF4A, eIF4E, and eIF4G. eIF4A functions to catalyze the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA facilitating ribosome scanning and translation initiation. The activation of oncogenic signaling pathways, including RAS and PI3K, facilitate formation of eIF4F and enhance eIF4A activity promoting the translation of oncogenes with highly structured 5’-UTRs that are required for tumor cell proliferation, survival and metastasis. eFT226 is a selective eIF4A inhibitor that converts eIF4A into a sequence specific translational repressor by increasing the affinity between eIF4A and 5’-UTR polypurine motifs leading to selective downregulation of mRNA translation. The polypurine element is highly enriched in the 5’-UTR of eFT226 target genes, many of which are known oncogenic drivers, including FGFR1,2 and HER2, enabling eFT226 to selectively inhibit dysregulated oncogene expression. Formation of a ternary complex [eIF4A-eFT226-mRNA] blocks ribosome scanning along the 5’-UTR leading to dose dependent inhibition of RTK protein expression. The 5’-UTR sequence dependency of eFT226 translational inhibition was evaluated in cell-based reporter assays demonstrating 10-45-fold greater sensitivity for reporter constructs containing an RTK 5’-UTR compared to a control. In solid tumor cell lines driven by alterations in FGFR1, FGFR2 or HER2, downregulation of RTK expression by eFT226 resulted in decreased MAPK and AKT signaling, potent inhibition of cell proliferation and an induction of apoptosis suggesting that eFT226 could be effective in treating tumor types dependent on these oncogenic drivers. Solid tumor xenograft models harboring FGFR1,2 or HER2 amplifications treated with eFT226 resulted in significant in vivo tumor growth inhibition and regression at well tolerated doses in breast, non-small cell lung and colorectal cancer models. Treatment with eFT226 also decreased RTK protein levels supporting the potential to use these eFT226 target genes as pharmacodynamic markers of target engagement. Further evaluation of predictive markers of sensitivity or resistance showed that RTK tumor models with mTOR mediated activation of eIF4A are most sensitive to eFT226. The association of eFT226 activity in RTK tumor models with mTOR pathway activation provides a means to further enrich for sensitive patient subsets during clinical development. Clinical trials with eFT226 in patients with solid tumor malignancies have initiated.
  • ternary complex formed blocks transcription selectively downregulating RTKs
  • drug binds in 5′ UTR and inhibits translation
  • RTKs activate eIF4 and are also transcribed through them so inhibition destroys this loop;  also with KRAS too
  • main antitumor activity are by an apoptotic mechanisms; refractory tumors are not sensitive to drug induced apoptosis
  • drug inhibits FGFR2 in colorectal cancer
  • drug also effective in HER2+ tumors
  • mTOR mediated eIF4 inhibited by drug
  • they get prolonged antitumor activity after washout of drug because forms this tight terniary complex

2:00 PM – 2:05 PM
– Discussion

2:05 PM – 2:15 PM
3400 – Adenosine receptor antagonists exhibit potent and selective off-target killing of FOXA1-high cancers: Steven M. Corsello, Ryan D. Spangler, Ranad Humeidi, Caitlin N. Harrington, Rohith T. Nagari, Ritu Singh, Vickie Wang, Mustafa Kocak, Jordan Rossen, Amael Madec, Nancy Dumont, Todd R. Golub. Dana-Farber Cancer Institute, Boston, MA, Broad Institute of MIT and Harvard, Cambridge, MA @corsellos

Abstract: Drugs targeting adenosine receptors were originally developed for the treatment of Parkinson’s disease and are now being tested in immuno-oncology clinical trials in combination with checkpoint inhibitors. We recently reported the killing activity of 4,518 drugs against 578 diverse cancer cell lines determined using the PRISM molecular barcoding approach. Surprisingly, three established adenosine receptor antagonists (CGS-15943, MRS-1220, and SCH-58261) showed potent and selective killing of FOXA1-high cancer cell lines without the need for immune cells. FOXA1 is a lineage-restricted transcription factor in luminal breast cancer, hepatocellular carcinoma, and prostate cancer without known small molecule inhibitors. We find that cytotoxic activity is limited to adenosine antagonists with a three-member aromatic core bound to a furan group, thus indicating a potential off-target mechanism of action. To identify genomic modulators of drug response, we performed genome-wide CRISPR/Cas9 knockout modifier screens. Killing by CGS-15943 and MRS-1220 was rescued by knockout of the aryl hydrocarbon receptor (AHR) and its nuclear partner ARNT. In confirmatory studies, knockout of AHR completely rescued killing by CGS-15943 in multiple cell types. Co-treatment with an AHR small molecule antagonist also rescued cell viability. Knockout of adenosine receptors did not alter drug response. Given that AHR is a known transcriptional regulator, we performed global mRNA sequencing to assess transcriptional changes induced by CGS-15943. The top two genes induced were the p450 enzymes CYP1A1 and CYP1B1. To determine sufficiency, we overexpressed CYP1A1 in a resistant cell line. Ectopic CYP1A1 expression sensitized to CGS-15943-mediated killing. Mass spectrometry revealed covalent trapping of a reactive metabolite by glutathione and potassium cyanide following in vitro incubation with liver microsomes. In addition, treatment of breast cancer cells with CGS-15943 for 24 hours resulted in increased γ-H2AX phosphorylation by western blot, indicative of DNA double stranded breaks. In summary, we identified off-target anti-cancer activity of multiple established adenosine receptor antagonists mediated by activation of AHR. Future studies will evaluate the functional contribution of FOXA1 and activity in vivo. Starting from a phenotypic screening hit, we leverage functional genomics to unlock the underlying mechanism of action. This project will pave the way for developing more effective therapies for biomarker-selected cancers, with potential to improve the care of patients with liver, breast, and prostate cancer.

  • developed a chemical library of over 6000 compounds (QC’d) to determine drugs that have antitumor effects
  • used a PRISM barcoded library to make cell lines to screen genotype-phenotype screens
  • for nononcology drugs fourteen drugs had activity in the PRISM assay
  • FOXA1 transcription factor high cancer cells seemed to be inhibited best with adenosine receptor inhibitor found in PRISM assay

2:15 PM – 2:20 PM
– Discussion

2:20 PM – 2:30 PM
3401 – Targeting lysosomal homeostasis in ovarian cancer through drug repurposing: Stefano Marastoni, Aleksandra Pesic, Sree Narayanan Nair, Zhu Juan Li, Ali Madani, Benjamin Haibe-Kains, Bradly G. Wouters, Anthony Joshua. University Health Network, Toronto, ON, Canada, Janssen Inc, Toronto, ON, Canada, The Kinghorn Cancer Centre, Sydney, Australia

Background: Drug repurposing has become increasingly attractive as it avoids the long processes and costs associated with drug discovery. Itraconazole (Itra) is a broad-spectrum anti-fungal agent which has an established broad spectrum of activity in human cell lines including cholesterol antagonism and inhibition of Hedgehog and mTOR pathways. Many in vitro, in vivo and clinical studies have suggested anti-proliferative activity both alone and in combination with other chemotherapeutic agents, in particular in ovarian cancer. This study is aimed at supporting the therapeutic potential of Itra and discovering and repurposing new drugs that can increase Itra anticancer activity as well as identifying new targets in the treatment of ovarian cancer.
Methods: We tested a panel of 32 ovarian cancer cell lines with different doses of Itra and identified a subset of cells which showed significant sensitivity to the drug. To identify genetic vulnerabilities and find new therapeutic targets to combine with Itra, we performed a whole genome sensitivity CRISPR screen in 2 cell lines (TOV1946 and OVCAR5) treated with non-toxic (IC10) concentrations of Itra.
Results: Pathway analysis on the top hits from both the screens showed a significant involvement of lysosomal compartments, and in particular dynamics between trans Golgi network and late endosomes/lysosomes, pathways that are affected by the autophagy inhibitor Chloroquine (CQ). We subsequently demonstrated that the combination of Itra and CQ had a synergistic effect in many ovarian cancer cell lines, even in those resistant to Itra. Further, genetic and pharmacological manipulation of autophagy indicated that upstream inhibition of autophagy is not a key mediator of the Itra/CQ mechanism of action. However, combination of Itra with other lysosomotropic agents (Concanamycin A, Bafilomycin A and Tamoxifen) displayed overlapping activity with Itra/CQ, supporting the lysosomal involvement in sensitizing cells to Itra resulted from the CRISPR screens. Analysis of lysosomal pattern and function showed a combined effect of Itra and CQ in targeting lysosomes and neutralizing their activity.
Conclusion: We identified two FDA approved drugs – CQ and Tamoxifen – that can be used in combination with Itra and exert a potent anti-tumor effect in ovarian cancer by affecting lyosomal function and suggesting a likely dependency of these cells on lysosomal biology. Further studies are in progress.

  • repurposing itraconozole in ovarian cancer potential mechanism of action is pleitropic
  • increasing doses of chloroquine caused OVCA cell death by accumulating in Golgi

2:30 PM – 2:35 PM
– Discussion

2:35 PM – 2:45 PM
3402 – BCAT1 as a druggable target in immuno-oncologyAdonia E. Papathanassiu, Francesca Lodi, Hagar Elkafrawy, Michelangelo Certo, Hong Vu, Jeong Hun Ko, Jacques Behmoaras, Claudio Mauro, Diether Lambrechts. Ergon Pharmaceuticals, Washington, DC, VIB Cancer Centre-KULeuven, Leuven, Belgium, Alexandria University, Alexandria, Egypt, University of Birmingham, Birmingham, United Kingdom, Ergon Pharmaceuticals, Washington, DC, Imperial College London, London, United Kingdom

2:45 PM – 2:50 PM
– Discussion

2:50 PM – 3:00 PM
3403 – Drugging the undruggable: Lessons learned from protein phosphatase 2A: Derek Taylor, Goutham Narla. Case Western Reserve University, Cleveland, OH, University of Michigan, Ann Arbor, MI @gouthamnarla

Abstract: Protein phosphatase 2A (PP2A) is a key tumor suppressor responsible for the dephosphorylation of many oncogenic signaling pathways. The PP2A holoenzyme is comprised of a scaffolding subunit (A), which serves as the structural platform for the catalytic subunit (C) and for an array of regulatory subunits (B) to assemble. Impairment of PP2A is essential for the pathogenesis of many diseases including cancer. In cancer, PP2A is inactivated through a variety of mechanisms including somatic mutation of the Aαsubunit. Our studies show that the most recurrent Aαmutation, P179R, results in an altered protein conformation which prevents the catalytic subunit from binding. Additionally, correcting this mutation, by expressing wild type PP2A Aαin cell lines harboring the P179R mutation, causes a reduction in tumor growth and metastasis. Given its central role in human disease pathogenesis, many strategies have been developed to therapeutically target PP2A.Our lab developed a series of small molecules activators of protein phosphatase 2A. One of our more advanced analogs in this series, DT-061, drives dephosphorylation and degradation of select pathogenic substrates of PP2A such as c-MYC in cellular and in vivo systems. Additionally, we have demonstrated the phosphomimetics of MYC that prevent PP2A mediated dephosphorylation and degradation markedly reduce the anti-tumorigenic activity of this series of PP2A activators further validating the target-substrate specificity of this approach. Specific mutations in the site of drug interaction or overexpression of the DNA tumor virus small T antigen which has been shown to specifically bind to and inactivate PP2A abrogate the in vivo activity of this small molecule series further validating the PP2A specificity of this approach. Importantly, treatment with DT-061 results in tumor growth inhibition in an array of in vivocancer models and marked regressions in combination with MEKi and PARPi.To further define the mechanism of action of this small molecule series, we have used cryo-electron microscopy (cryo-EM) to visualize directly theinteraction between DT-061 and a PP2A heterotrimeric complex. We have identified molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme through the marked prolongation of the kOFF of the native complex. Furthermore, we demonstrate that DT-061 specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate oncogenic targets such as c-MYC in both cellular and in vivo systems. This 3.6 Å structure identifies dynamic molecular interactions between the three distinct PP2A subunits and highlight the inherent mechanisms of PP2A complex assembly and disassembly in both cell free and cellular systems. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for the therapeutic targeting of previously undruggable proteins, and aid in the development of phosphatase-based therapeutics tailored against disease specific phosphor-protein targets. The marriage of multidisciplinary scientific practices has allowed us to present here a previously unrecognized therapeutic strategy of complex stabilization for the activation of endogenous disease combating enzymes.

  • Reactivating PP2A; dephosphorylation of proteins (serine/threonine phosphatases); regulates multiple processes in the cell
  • SV40T has an antigen that inactivates PP2A; recurrent mutations in high grade endometrial cancers
  • P179R mutation promotes uterine tumor formation (also in a distal tubule ligation model)
  • project started in a phenotypic screen that tricyclic antidepressants could have an off target which was phosphatase activators (uncoupling GPCR from anticancer activity)
  • small T antigen block the activity of these small molecule activators;
  • acts as a molecular glue to bring the activators with a heterotrimer of phosphatases
  • so their small molecule activators effective in triple negative breast cancers;  one of targets of PP2A is MYC
  • question: have not yet seen resistance to these compounds but are currently looking at this

 

3:00 PM – 3:05 PM
– Discussion

3:05 PM – 3:15 PM
3404 – Inhibition of BCL10-MALT1 interaction to treat diffuse large B-cell lymphomaH: eejae Kang, Dong Hu, Marcelo Murai, Ahmed Mady, Bill Chen, Zaneta Nikolovska-Coleska, Linda M. McAllister-Lucas, Peter C. Lucas. University of Pittsburgh School of Medicine, Pittsburgh, PA, Merck, Kenilworth, NJ, University of Michigan School of Medicine, Ann Arbor, MI, University of Pittsburgh School of Medicine, Pittsburgh, PA, University of Michigan School of Medicine, Ann Arbor, MI, UPMC Children’s Hospital, Pittsburgh, PA

Abstract: The CARMA1/BCL10/MALT1 (CBM) signaling complex mediates antigen receptor-induced activation of NF-kB in lymphocytes to support normal adaptive immunity. As the effector protein of the complex, MALT1 exhibits two activities: protease and scaffolding activities. Gain-of-function mutations in the CARMA1 moiety or its upstream regulators trigger antigen-independent assembly of oligomeric CBM complexes, leading to constitutive activation of MALT1, unregulated NF-kB activity, and development of Activated B-Cell subtype of Diffuse Large B-Cell Lymphoma (ABC-DLBCL). Existing MALT1 inhibitors block only MALT1 protease activity, causing incomplete and unbalanced inhibition of MALT1, and have the potential for inducing autoimmune side effects. Since MALT1 is recruited to the CBM complex via its interaction with BCL10, we sought to identify inhibitors of BCL10-MALT1 interaction in order to target both the protease and scaffolding activities of MALT1 to treat ABC-DLBCL.
Our previous work suggested that an antibody-epitope-like interface governs the interaction between BCL10 and MALT1, so that a therapeutic opportunity exists for developing a small molecule inhibitor of the interaction to terminate inappropriate CBM activity. Using co-immunoprecipitation studies, a mammalian two-hybrid system, and surface plasmon resonance (SPR), we confirmed that BCL10 residues 107-119 and the tandem Ig-like domains of MALT1 are critical for this interaction. We then performed a structure-guided in silico screen of 3 million compounds, based on a computational model of the BCL10-MALT1 interaction interface, to identify compounds with potential for disrupting the interaction.
Compound 1 from the initial screening hits showed dose-responsive inhibition of BCL10-MALT1 interaction in both SPR and ELISA-based assays. Functionally, Compound 1 inhibits both MALT1 protease and scaffolding activities in Jurkat T cells, as demonstrated by its inhibition of CD3/CD28-induced RelB and N4BP1 cleavage, and inhibition of IKK phosphorylation, respectively. Compound 1 also blocks IL-2 transcription and IL-2 secretion by PMA/ionomycin-treated Jurkat T cells, as well as constitutive CBM-dependent secretion of IL-6 and IL-10 by ABC-DLBCL cells. Accordingly, Compound 1 selectively suppresses the growth of ABC-DLBCL cell lines, but does not affect the growth of MALT1-independent GCB-DLBCL cell lines.
In conclusion, we have identified an early-stage small molecule compound that inhibits the BCL10-MALT1 interaction, MALT1 protease and scaffolding activities, downstream CBM-dependent signaling, and ABC-DLBCL cell growth. Structure-guided modification of this lead compound is underway to further develop a new class of protein-protein interaction inhibitors that could provide more efficacious blockade of MALT1, while offering protection from undesirable autoimmune side effects in the treatment of this aggressive form of lymphoma.

3:15 PM – 3:20 PM
– Discussion

3:20 PM – 3:30 PM
– Closing RemarksJohn S. Lazo. University of Virginia, Charlottesville, VA

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Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

 

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

 

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

 

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

 

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

 

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

 

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

 

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

 

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

 

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

 

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

 

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

 

References:

 

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

 

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

 

https://www.pnas.org/content/115/18/4743

 

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

 

https://cshperspectives.cshlp.org/content/10/5/a028795

 

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Gender of a person can affect the kinds of cancer-causing mutations they develop, according to a genomic analysis spanning nearly 2,000 tumours and 28 types of cancer. The results show striking differences in the cancer-causing mutations found in people who are biologically male versus those who are biologically female — not only in the number of mutations lurking in their tumours, but also in the kinds of mutations found there.

 

Liver tumours from women were more likely to carry mutations caused by a faulty system of DNA mending called mismatch repair, for instance. And men with any type of cancer were more likely to exhibit DNA changes thought to be linked to a process that the body uses to repair DNA with two broken strands. These biases could point researchers to key biological differences in how tumours develop and evolve across sexes.

 

The data add to a growing realization that sex is important in cancer, and not only because of lifestyle differences. Lung and liver cancer, for example, are more common in men than in women — even after researchers control for disparities in smoking or alcohol consumption. The source of that bias, however, has remained unclear.

In 2014, the US National Institutes of Health began encouraging researchers to consider sex differences in preclinical research by, for example, including female animals and cell lines from women in their studies. And some studies have since found sex-linked biases in the frequency of mutations in protein-coding genes in certain cancer types, including some brain cancers and advanced melanoma.

 

But the present study is the most comprehensive study of sex differences in tumour genomes so far. It looks at mutations not only in genes that code for proteins, but also in the vast expanses of DNA that have other functions, such as controlling when genes are turned on or off. The study also compares male and female genomes across many different cancers, which can allow researchers to pick up on additional patterns of DNA mutations, in part by increasing the sample sizes.

 

Researchers analysed full genome sequences gathered by the International Cancer Genome Consortium. They looked at differences in the frequency of 174 mutations known to drive cancer, and found that some of these mutations occurred more frequently in men than in women, and vice versa. When they looked more broadly at the loss or duplication of DNA segments in the genome, they found 4,285 sex-biased genes spread across 15 chromosomes.

 

There were also differences found when some mutations seemed to arise during tumour development, suggesting that some cancers follow different evolutionary paths in men and women. Researchers also looked at particular patterns of DNA changes. Such patterns can, in some cases, reflect the source of the mutation. Tobacco smoke, for example, leaves behind a particular signature in the DNA.

 

Taken together, the results highlight the importance of accounting for sex, not only in clinical trials but also in preclinical studies. This could eventually allow researchers to pin down the sources of many of the differences found in this study. Liver cancer is roughly three times as common in men as in women in some populations, and its incidence is increasing in some countries. A better understanding of its aetiology may turn out to be really important for prevention strategies and treatments.

 

References:

 

https://www.nature.com/articles/d41586-019-00562-7?utm_source=Nature+Briefing

 

https://www.nature.com/news/policy-nih-to-balance-sex-in-cell-and-animal-studies-1.15195

 

https://www.ncbi.nlm.nih.gov/pubmed/26296643

 

https://www.biorxiv.org/content/10.1101/507939v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25985759

 

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Immunoediting can be a constant defense in the cancer landscape


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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Immunotherapy may help in glioblastoma survival


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. But, in a glimmer of hope, a recent study found that a drug designed to unleash the immune system helped some patients live longer. Glioblastoma powerfully suppresses the immune system, both at the site of the cancer and throughout the body, which has made it difficult to find effective treatments. Such tumors are complex and differ widely in their behavior and characteristics.

 

A small randomized, multi-institution clinical trial was conducted and led by researchers at the University of California at Los Angeles involved patients who had a recurrence of glioblastoma, the most common central nervous system cancer. The aim was to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab (checkpoint inhibitor) in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone.

 

Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhanced both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

 

Immunotherapy has not proved to be effective against glioblastoma. This small clinical trial explored the effect of PD-1 blockade on recurrent glioblastoma in relation to the timing of administration. A total of 35 patients undergoing resection of recurrent disease were randomized to either neoadjuvant or adjuvant pembrolizumab, and surgical specimens were compared between the two groups. Interestingly, the tumoral gene expression signature varied between the two groups, such that those who received neoadjuvant pembrolizumab displayed an INF-γ gene signature suggestive of T-cell activation as well as suppression of cell-cycle signaling, possibly consistent with growth arrest. Although the study was not powered for efficacy, the group found an increase in overall survival in patients receiving neoadjuvant pembrolizumab compared with adjuvant pembrolizumab of 13.7 months versus 7.5 months, respectively.

 

In this small pilot study, neoadjuvant PD-1 blockade followed by surgical resection was associated with intratumoral T-cell activation and inhibition of tumor growth as well as longer survival. How the drug works in glioblastoma has not been totally established. The researchers speculated that giving the drug before surgery prompted T-cells within the tumor, which had been impaired, to attack the cancer and extend lives. The drug didn’t spur such anti-cancer activity after the surgery because those T-cells were removed along with the tumor. The results are very important and very promising but would need to be validated in much larger trials.

 

References:

 

https://www.washingtonpost.com/health/2019/02/11/immunotherapy-may-help-patients-with-kind-cancer-that-killed-john-mccain/?noredirect=on&utm_term=.e1b2e6fffccc

 

https://www.ncbi.nlm.nih.gov/pubmed/30742122

 

https://www.practiceupdate.com/content/neoadjuvant-anti-pd-1-immunotherapy-promotes-immune-responses-in-recurrent-gbm/79742/37/12/1

 

https://www.esmo.org/Oncology-News/Neoadjuvant-PD-1-Blockade-in-Glioblastoma

 

https://neurosciencenews.com/immunotherapy-glioblastoma-cancer-10722/

 

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TWEETS by @pharma_BI and @AVIVA1950 at #IESYMPOSIUM – @kochinstitute 2019 #Immune #Engineering #Symposium, 1/28/2019 – 1/29/2019

 

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

 

eProceedings for Day 1 and Day 2

LIVE Day One – Koch Institute 2019 Immune Engineering Symposium, January 28, 2019, Kresge Auditorium, MIT

https://pharmaceuticalintelligence.com/2019/01/28/live-day-one-koch-institute-2019-immune-engineering-symposium-january-28-2019-kresge-auditorium-mit/

 

LIVE Day Two – Koch Institute 2019 Immune Engineering Symposium, January 29, 2019, Kresge Auditorium, MIT

https://pharmaceuticalintelligence.com/2019/01/29/live-day-two-koch-institute-2019-immune-engineering-symposium-january-29-2019-kresge-auditorium-mit/

 

 

  1. AMAZING Conference I covered in Real Time

  2. Aviv Regev Melanoma: malignant cells with resistance in cold niches in situ cells express the resistance program pre-treatment: resistance UP – cold Predict checkpoint immunotherapy outcomes CDK4/6 abemaciclib in cell lines

  3. Aviv Regev, a cell-cell interactions from variations across individuals Most UC-risk genes are cell type specificVariation – epithelial cell signature – organize US GWAS into cell type spec

  4. Diane Mathis Age-dependent Treg and mSC changes – Linear with increase in age Sex-dependent Treg and mSC changes – Female Treg loss in cases of Obesity leading to fibrosis Treg keep IL-33-Producing mSCs under rein Lean tissue/Obese tissue

  5. Martin LaFleur Loss of Ptpn2 enhances CD8+ T cell responses to LCMV and Tumors PTpn2 deletion in the immune system enhanced tumor immunity CHIME enables in vivo screening

  6. Alex Shalek Identifying and rationally modulating cellular drivers of enhanced immunity T Cells, Clusters Expression of Peak and Memory Immunotherapy- Identifying Dendritic cells enhanced in HIV-1 Elite Controllers

  7.   Retweeted

    Onward: our own Michael Birnbaum, who assures us that if you feel like you’re an immunoengineer, then you ARE one!

  8. Glenn Dranoff Adenosine level in blood or tissue very difficult to measure in blood even more than in tissue – NIR178 + PDR 001 Monotherapy (NIR178) combine with PD receptor blockage (PDR) show benefit A alone vs A+B in Clinical trial

  9. Glenn Dranoff PD-L1 blockade elicits responses in some patients: soft part sarcoma LAG-3 combined with PD-1 – human peripheral blood tumor TIM-3 key regulator of T cell and Myeloid cell function: correlates in the TCGA DB myeloid

  10. Glenn Dranoff Institute for Biomedical Research of Neurologic toxicities of CART t IL-6 activation AML – complete response – weekly dose of XmAb CD123X CD3 bispecific antibody anti tumor effect

  11. of protective HLA-DR4 effects outside of “peptide anchor” residues Class I MHC – HLA-E down regulate T and NK cells Receptor Binding: Positional preferences noted for NKG2A

  12. Yvonne Chen Activation of t Cell use CAR t Engineer CAR-T to respond to soluble form of antigens: CD19 CAR Responds to soluble CD19 GFP MCAR responds to Dimeric GFP “Tumor microenvironment is a scary place”

  13. Yvonne Chen Do we need a ligand to be a dimers? Co-expressed second-generation TGF-beta signaling

  14. Yvonne Chen “Engineering smarter and stronger T cells for cancer immunotherapy” OR-Gate cause no relapse – Probing limits of modularity in CAR Design Bispecific CARs are superior to DualCAR: One vs DualCAR (some remained single CAR)

  15.   Retweeted

    Ending the 1st session is Cathy Wu of detailing some amazing work on vaccination strategies for melanoma and glioblastoma patients. They use long peptides engineered from tumor sequencing data.

  16.   Retweeted

    Some fancy imaging: Duggan gives a nice demo of how dSTORM imaging works using a micropatterend image of Kennedy Institute for Rheumatology! yay!

  17.   Retweeted

    Lots of interesting talks in the second session of the – effects of lymphoangiogenesis on anti-tumor immune responses, nanoparticle based strategies to improve bNAbs titers/affinity for HIV therapy, and IAPi cancer immunotherapy

  18.   Retweeted

    Looking forward to another day of the . One more highlight from yesterday – from our own lab showcased her work developing cytokine fusions that bind to collagen, boosting efficacy while drastically reducing toxicities

  19.   Retweeted

    Members of our cell therapy team were down the street today at neighboring for the presented by .

  20.   Retweeted

    He could have fooled me that he is, in fact, an immunologist!

  21.  
  22.   Retweeted

    Come and say Hi! ACIR will be back tomorrow at the Immune Engineering Symposium at MIT. Learn more at . . And stay tuned to read our summary of the talks on Feb 6.

  23. Facundo Batista @MGH # in BG18 Germline Heavy CHain (BG18-gH) High-mannose patch – mice exhibit normal B cell development B cells from naive human germline BG18-gH bind to GT2 immunogen

  24. Preeti Sharma, U Illinois T cell receptor and CAR-T engineering TCR engineering for Targeting glycosylated cancer antigens Nornal glycosylation vs Aberrant Engineering 237-CARs libraries with conjugated (Tn-OTS8) against Tn-antigend In vitro

  25. Bryan Bryson Loss of polarization potential: scRNAseq reveals transcriptional differences Thioredoxin facilitates immune response to Mtb is a marker of an inflammatory macrophage state functional spectrum of human microphages

  26. Bryan Bryson macrophage axis in Mycobacterium tuberculosis Building “libraries” – surface marker analysis of Microphages Polarized macrophages are functionally different quant and qual differences History of GM-CSF suppresses IL-10

  27. Jamie Spangler John Hopkins University “Reprogramming anti-cancer immunity RESPONSE through molecular engineering” De novo IL-2 potetiator in therapeutic superior to the natural cytokine by molecular engineering mimicking other cytokines

  28. Jamie Spangler JES6-1 Immunocytokine – inhibiting melanoma Engineering a Treg cell-biased immunocytokine double mutant immunocytokine shows enhanced IL-2Ralpha exchange Affinity De Novo design of a hyper-stable, effector biased IL-2

  29. , Volume Five: in of Cardiovascular Diseases. On com since 12/23/2018

  30. Michael Dustin ESCRT pathway associated with synaptic ectosomes Locatization, Microscopy Cytotoxic T cell granules CTLs release extracellular vescicles similar to T Helper with perforin and granzyme – CTL vesicles kill targets

  31. Michael Dustin Delivery of T cell Effector function through extracellular vesicles Synaptic ectosome biogenisis Model: T cells: DOpamine cascade in germinal cell delivered to synaptic cleft – Effector CD40 – Transfer is cooperative

  32. Michael Dustin Delivery of T cell Effector function through extracellular vesicles Laterally mobile ligands track receptor interaction ICAM-1 Signaling of synapse – Sustain signaling by transient in microclusters TCR related Invadipodia

  33. Mikael Pittet @MGH Myeloid Cells in Cancer Indirect mechanism AFTER a-PD-1 Treatment IFN-gamma Sensing Fosters IL-12 & therapeutic Responses aPD-1-Mediated Activation of Tumor Immunity – Direct activation and the ‘Licensing’ Model

  34. Stefani Spranger KI Response to checkpoint blockade Non-T cell-inflamed – is LACK OF T CELL INFILTRATION Tumor CD103 dendritic cells – Tumor-residing Batf3-drivenCD103 Tumor-intrinsic Beta-catenin mediates lack of T cell infiltration

  35. Max Krummel Gene expression association between two genes: and numbers are tightly linked to response to checkpoint blockage IMMUNE “ACCOMODATION” ARCHYTYPES: MYELOID TUNING OF ARCHITYPES Myeloid function and composition

  36. Noor Momin, MIT Lumican-cytokines improve control of distant lesions – Lumican-fusion potentiates systemic anti-tumor immunity

    Translate Tweet

  37. Noor Momin, MIT Lumican fusion to IL-2 improves treatment efficacy reduce toxicity – Anti-TAA mAb – TA99 vs IL-2 Best efficacy and least toxicity in Lumican-MSA-IL-2 vs MSA-IL2 Lumican synergy with CAR-T

  38.   Retweeted

    excited to attend the immune engineering symposium this week! find me there to chat about and whether your paper could be a good fit for us! 🦠🧬🔬🧫📖

  39.   Retweeted

    Bob Schreiber and Tyler Jacks kicked off the with 2 great talks on the role of Class I and Class II neo-Ag in tumor immunogenicity and how the tumor microenvironment alters T cell responsiveness to tumors in vivo

  40.   Retweeted

    Scott Wilson from gave a fantastic talk on glycopolymer conjugation to antigens to improve trafficking to HAPCs and enhanced tolerization in autoimmunity models. Excited to learn more about his work at his faculty talk!

  41. AMAZING Symposinm

  42.   Retweeted

    Immune Engineering Symposium at MIT is underway!

  43.   Retweeted

    ACIR is excited to be covering the Immune Engineering Symposium at MIT on January 28-29. Learn more at .

  44. Tyler Jacks talk was outstanding, Needs be delivered A@TED TALKs, needs become contents in the curriculum of Cell Biology graduate seminar as an Online class. BRAVO

  45.   Retweeted

    Here we go!! Today and tomorrow the tippity top immunologists converge at

  46.   Retweeted

    Exciting start to this year’s Immune Engineering Symposium put on by at . A few highlights from the first section…

  47. Stephanie Dougan (Dana-Farber Cancer Institute) Dept. Virology IAPi outperforms checkpoint blockade in T cell cold tumors reduction of tumor burden gencitabine cross-presenting DCs and CD8 T cells – T cell low 6694c2

  48. Darrell Irvine (MIT, Koch Institute; HHMI) Engineering follicle delivery through synthetic glycans: eOD-60mer nanoparticles vs Ferritin-trimer 8-mer (density dependent)

  49. Darrell Irvine (MIT, Koch Institute; HHMI) GC targeting is dependent on complement component CIQ – activation: Mannose-binding lectins recognize eOD-60mer but not eOD monomer or trimers

  50. Melody Swartz (University of Chicago) Lymphangiogenesis attractive to Native T cells, in VEGF-C tumors T cell homing inhibitors vs block T cell egress inhibitors – Immunotherapy induces T cell killing

  51. Cathy Wu @MGH breakthrough for Brain Tumor based neoantigen-specific T cell at intracranial site Single cells brain tissue vs single cells from neoantigen specific T cells – intratumoral neoantigen-specific T cells: mutARGAP35-spacific

  52. Cathy Wu (Massachusetts General Hospital) – CoFounder of NEON Enduring complete radiographic responses after + alpha-PD-1 treatment (anti-PD-1) NeoVax vs IVAC Mutanome for melanoma and Glioblastoma clinical trials

  53. , U of Chicago IV INJECTION: OVAALBUMIN OVA-P(GALINAC), P(GLCNAC), SUPRESS T CELL RESPONSE Abate T cells response – Reduced cytokine production & increased -regs

  54. Interrogating markers of T cell dysfunction – chance biology of cells by CRISPR – EGR2 at 2 weeks dysfuntioning is reduced presence of EDR2 mutant class plays role in cell metabolism cell becomes functional regulator CD8 T cell

  55. Bob Schreiber (Wash University of St. Louis) Optimal CD8+ T cells mediated to T3 require CD4+ T help

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LIVE Day Two – Koch Institute 2019 Immune Engineering Symposium, January 29, 2019, Kresge Auditorium, MIT

 

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

#IESYMPOSIUM @pharma_BI @AVIVA1950

 

MISSION The mission of the Koch Institute (KI) is to apply the tools of science and technology to improve the way cancer is detected, monitored, treated and prevented.

APPROACH We bring together scientists and engineers – in collaboration with clinicians and industry partners – to solve the most intractable problems in cancer. Leveraging MIT’s strengths in technology, the life sciences and interdisciplinary research, the KI is pursuing scientific excellence while also directly promoting innovative ways to diagnose, monitor, and treat cancer through advanced technology.

HISTORY The Koch Institute facility was made possible through a $100 million gift from MIT alumnus David H. Koch. Our new building opened in March 2011, coinciding with MIT’s 150th anniversary. Our community has grown out of the MIT Center for Cancer Research (CCR), which was founded in 1974 by Nobel Laureate and MIT Professor Salvador Luria, and is one of seven National Cancer Institute-designated basic (non-clinical) research centers in the U.S.

https://ki.mit.edu/files/ki/cfile/news/presskit/KI_Fact_Sheet_-_February_2018.pdf

January 28-29, 2019
Kresge Auditorium, MIT

Biological, chemical, and materials engineers are engaged at the forefront of immunology research. At their disposal is an analytical toolkit honed to solve problems in the petrochemical and materials industries, which share the presence of complex reaction networks, and convective and diffusive molecular transport. Powerful synthetic capabilities have also been crafted: binding proteins can be engineered with effectively arbitrary specificity and affinity, and multifunctional nanoparticles and gels have been designed to interact in highly specific fashions with cells and tissues. Fearless pursuit of knowledge and solutions across disciplinary boundaries characterizes this nascent discipline of immune engineering, synergizing with immunologists and clinicians to put immunotherapy into practice.

The 2019 symposium will include two poster sessions and four abstract-selected talks. Abstracts should be uploaded on the registration page. Abstract submission deadline is November 15, 2018. Registration closes December 14.

Featuring on Day 2, 1/29, 2019:

Session IV

Moderator: Michael Birnbaum, Koch Institute, MIT

 

Jamie Spangler (John Hopkins University)

“Reprogramming anti-cancer immunity through molecular engineering”

  • Reprogramming anti-cancer immunity response through molecular engineering”
  • Cytokines induce receptor dimerization
  • Clinical Use of cytokines: Pleiotropy, expression and stability isssues
  • poor pharmacological properties
  • cytokine therapy: New de novo protein using computational methods
  • IL-2 signals through a dimeric nad a trimeric receptor complex
  • IL-2 pleiotropy hinders its therapeutic efficacy
  • IL-2 activate immunosuppression
  • potentiation of cytokine activity by anti-IL-2 antibody selectivity
  • Cytokine binding – Antibodies compete with IL-2 receptor subunits
  • IL-2Ralpha, IL-2 Rbeta: S4B6 mimickry of alpha allosterically enhances beta
  • stimulates both Effectors and T-regs
  • JES6-1 immunocomplex selectively stimulates IL-2Ralpha cells
  • Engineering translational single-chain cytokine/antibody fusion
  • Engineering an EFFECTOR cell-based immunocytokine (602)
  • JES6-1 Immunocytokine – inhibiting melanoma
  • Engineering a Treg cell-biased immunocytokine
  • double mutant immunocytokine shows enhanced IL-2Ralpha exchange
  • Affinity  – molecular eng De Novo design of a hyper-stable, effector biased IL-2
  • De novo IL-2 poteniator in therapeutic superior to the natural cytokine by molecular engineering

 

Bryan Bryson (MIT, Department of Biological Engineering)

“Exploiting the macrophage axis in Mycobacterium tuberculosis (Mtb) infection”

  • TB  – who develop Active and why?
  • Immunological life cycle of Mtb
  • Global disease Mtb infection outcome varies within individual host
  • lesion are found by single bacteria
  • What are the cellular players in immune success
  • MACROPHAGES – molecular signals enhancing Mtb control of macrophages
  • modeling the host- macrophages are plastic and polarize
  • Building “libraries” – surface marker analysis of Microphages
  • Polarized macrophages are functionally different
  • quant and qual differences
  • History of GM-CSF suppresses IL-10
  • Loss of polarization potential: scRNAseq reveals transcriptional differences Thioredoxin facilitates immune response to Mtb is a marker of an inflammatory macrophage state
  • functional spectrum of human microphages

 

Facundo Batista (Ragon Institute (HIV Research) @MGH, MIT and Harvard)

“Vaccine evaluation in rapidly produced custom humanized mouse models”

  • Effective B cell activation requires 2 signals Antigen and binding to T cell
  • VDJ UCA (Unmutated common Ancestor)
  • B Cell Receptor (BCR) co-receptors and cytoskeleton
  • 44% in Women age 24-44
  • Prototype HIV broadly neutralizing Antibodies (bnAb) do not bind to Env protein – Immunogen design and validation
  • Target Identification –>> Immunogen Design –>>> Immunogen Validation
  • Human Ig Knock-ins [Light variable 5′ chain length vs 7′ length] decisive to inform immunogenicity – One-Step CRISPR approach does not require ES cell work
  • Proof of principle with BG18 Germline Heavy Chain (BG18-gH) High-mannose patch – mice exhibit normal B cell development
  • B cells from naive human germline BG18-gH bind to GT2 immunogen
  • GT2-nanoparticle 9NP) induces robust BG18-gH-500 cells: CD45.2 GL7 IgD
  • Interrogate immune response for HIV, Malaria, Zika, Flu

 

Session V

Moderator: Dane Wittrup, Koch Institute, MIT

 

Yvonne Chen (University of California, Los Angeles)

“Engineering smarter and stronger T cells for cancer immunotherapy”

  • Adoptive T-Cell Therapy
  • Tx for Leukemia – Tumor Antigen escape fro CAR T-cell therapy, CD19/CD20 OR-Gate CARs for prevention of antigen escape – 15 month of development
  • reduce probability of antigen escape due to two antigen CD19/CD20: Probing limits of modularity in CAR design
  • In vivo model: 75% wild type & 25% CD19 – relapse occur in the long term, early vs late vs no relapse: Tx with CAR t had no relapse
  • OR-Gate cause no relapse – Probing limits of modularity in CAR Design
  • Bispecific CARs are superior to DualCAR: One vs DualCAR (some remained single CAR)
  • Bispecific CARs exhibit superior antigen-stimulation capacity – OR-Gate CAR Outperforms Single-Input CARs
  • Lymphoma and Leukemia are 10% of all Cancers
  • TGF-gamma Rewiring T Cell Response
  • Activation of t Cell use CAR t
  • Engineer CAR-T to respond to soluble form of antigens: CD19 CAR Responds to soluble CD19
  • GFP MCAR responds to Dimeric GFP
  • “Tumor microenvironment is a scary place”

 

Michael Birnbaum, MIT, Koch Institute

“A repertoire of protective tumor immunity”

  • Decoding T and NK cell recognition – understanding immune recognition and signaling function for reprogramming the Immune system – Neoantigen vaccine pipeline
  • Personal neoantigen vax improve immunotherapy
  • CLASS I and CLASS II epitomes: MHC prediction performance – more accurate for CLASS I HLA polymorphisms
  • Immune Epitope DB and Analysis Resources 448,630 Peptide Epitomes
  • B cell assay: 413,000
  • T cell assays: 313,000
  • peptide sequence relationships – naturally occurring antigen predictions
  • Cleavable pMHC yeast display to determine peptide loading
  • HLA-DR4 libraries enrich a large collection of peptides: 96000 1/5 of entire peptide DB: Enriched motif, prediction algorithms
  • Algorithmic false negatives vs peptide concentration(nM)
  • HLA-DR4 effects outside of “peptide anchor” residues
  • Class I MHC – HLA-E down regulate T and NK cells
  • Receptor Binding: Positional preferences noted for NKG2A
  • Training data vs Algorithmic approach
  • Globally oriented –
  • TCR sequencing – TCR pairings – Multicell-per-well sequencing
  • MAD-HYPE algorithm

 

Glenn Dranoff, Novartis Institute for Biomedical Research

“Mechnism of protective tumor immunity”

  • Immune checkpoint blockade elicit 10 years survival in melanoma
  • PD-1 blockage esophageal carcinoma effective showing survival
  • renal cells, bladder
  • 20% benefit from Immuno therapy – CTLA-4 toxicity is high small % patient benefit
  • PD-1/PD-L1 anti CLTA-4 mAbs
  • solid tumors challenging
  • Requirement for effective IO – Tumor receptivity to immune infiltration
  • modulation
  • Novartis IO in the clinic: multiple tumor immune escape – complexity
  • Approach: focus trials aimed to learn immune response complementation groups manipulate into response
  • work with Engineering for delivery nimble to generate new data
  • Translational research in the clinic
  • CAR T cells
  • B cell malignancies are ideal targets for CAR T cells
  • Relapsed/Refractory – pediatric ALL refractory advanced to no relapse – complete response 80% – 6 years response
  • Antigen loss CD19 – targeting with combinatorial approach to avoid relapse
  • Large B cell lymphoma
  • Neurologic toxicities of CART t IL-6 activation
  • AML – complete response – weekly dose of XmAb CD123X CD3 bispecific antibody – protein engineering – anti tumor effect in refractory Leukemia
  • anaplastic thyroid carcinoma
  • PD-L1 blockade elicits responses in some patients: soft part sarcoma
  • LAG-3 combined with PD-1 – human peripheral blood tumor
  • TIM-3 key regulator of T cell and Myeloid cell function: correlates in the TCGA DB with myeloid
  • Adenosine level in blood or tissue very difficult to measure in blood even more than in tissue – NIR178 + PDR 001 Mono-therapy (NIR178) combine with PD receptor blockage (PDR) – shows benefit
  • A alone vs A+B in Clinical trial

 

Session VI

Moderator: Stefani Spranger, Koch Institute, MIT

 

Tim Springer, Boston Children’s Hospital, HMS

The Milieu Model for TGF-Betta Activation”

  • Protein Science – Genomics with Protein
  • Antibody Initiative – new type of antibodies not a monoclonal antibody – a different type
  • Pro TGF-beta
  • TGF-beta – not a typical cytokine it is a prodamine for Mature growth factor — 33 genes mono and heterogeneous dimers
  • Latent TGF-Beta1 crystal structure: prodomaine shields the Growth Factor
  • Mechanism od activation of pro-TGF-beta – integrin alphaVBeta 6: pro-beta1:2
  • Simulation in vivo: actin cytoskeleton cytoplasmic domain
  • LIFE CYCLE OF PROTGF-BETA
  • LRRC33 – GARP class relative
  • microglia and macrophage – link TGF-beta phenotype knock outs
  • TGF compartments of microglia separated myelination loss
  • Inhibition of TGF-beta enhances immune checkpoint
  • Loss of LRRC33-dependent TGF-beta signaling would counteract immune suppression in tumor and in slow tumor growth
  • lung metastasis of B16 in melanoma
  • immuno-histo-chemistry: LRRC33 tumor-associated myeloid cell lack cell surface proTGF-beta1
  • blocking antibodies LRRC33 mitigate toxicity on PD-L1 treatment

 

Alex Shalek, MIT, Department of Chemistry, Koch Institute

“Identifying and rationally modulating cellular drivers of enhanced immunity”

  • Balance in the Immune system
  • Profiling Granulomas  using Seq-Well 2.0
  • lung tissue in South Africa of TB patients
  • Granulomas, linking cell type abundance with burden
  • Exploring T cells Phenotypes
  • Cytotoxic & Effector ST@+ Regulatory
  • Vaccine against TB – 19% effective, only 0 IV BCG vaccination can elicit sterilizing Immunity
  • Profiling cellular response to vaccination
  • T cell gene modules across vaccine routes
  • T Cells, Clusters
  • Expression of Peak and Memory
  • Immunotherapy- Identifying Dendritic cells enhanced in HIV-1 Elite Controllers
  • moving from Observing to Engineering
  • Cellular signature: NK-kB Signaling
  • Identifying and testing Cellular Correlates of TB Protection
  • Beyond Biology: Translation research: Data sets: dosen

 

Session VII

Moderator: Stefani Spranger, Koch Institute, MIT

 

Diane Mathis, Harvard Medical School

“Tissue T-regs”

  • T reg populations in Lymphoid Non–lymphoid Tissues
  • 2009 – Treg tissue homeostasis status – sensitivity to insulin, 5-15% CD4+ T compartment
  •  transcriptome
  • expanded repertoires TCRs
  • viceral adipose tissue (VAT) –  Insulin
  • Dependencies: Taget IL-33 its I/1r/1 – encoded Receptor ST2
  • VAT up-regulate I/1r/1:ST2 Signaling
  • IL-33 – CD45 negative CD31 negative
  • mSC Production of IL-33 is Important to Treg
  • The mesenchyme develops into the tissues of the lymphatic and circulatory systems, as well as the musculoskeletal system. This latter system is characterized as connective tissues throughout the body, such as bone, muscle and cartilage. A malignant cancer of mesenchymal cells is a type of sarcoma.
  • mesenchymal Stromal Cells – mSC – some not all, VAT mSCs express IL-33
  • development of a mAb Panel for sorting the mSC Subtypes
  • Deeper transcriptome for Phenotyping of VAT mSCs
  • physiologic & pathologic perturbation
  1. Age-dependent Treg and mSC changes – Linear with increase in age
  2. Sex-dependent Treg and mSC changes – Female
  • Treg loss in cases of Obesity leading to fibrosis
  • Treg keep IL-33-Producing mSCs under rein
  • Lean tissue vs Obese tissue
  • Aged mice show poor skeletal muscle repair – it is reverses by IL-33 Injection
  • Immuno-response: target tissues systemic T reg
  • Treg and mSC

 

Aviv Regev, Broad Institute; Koch Institute

“Cell atlases as roadmaps to understand Cancer”

  • Colon disease UC – genetic underlining risk, – A single cell atlas of healthy and UC colonic mucosa inflammed and non-inflammed: Epithelial, stromal, Immune – fibroblast not observed in UC colon IAFs; IL13RA2 + IL11
  • Anti TNF responders – epithelial cells
  • Anti TNF non-responders – inflammatory monocytes fibroblasts
  • RESISTANCE to anti-cancer therapy: OSM (Inflammatory monocytes-OSMR (IAF)
  • cell-cell interactions from variations across individuals
  • Most UC-risk genes are cell type specific
  • Variation within a cell type helps predict GWAS gene functions – epithelial cell signature – organize US GWAS into cell type specific – genes in associated regions: UC and IBD

 

  • Melanoma
  • malignant cells with resistance in cold niches in situ
  • cells express the resistance program pre-treatment: resistance UP – cold
  • Predict checkpoint immunotherapy outcomes
  • CDK4/6 – computational search predict as program regulators: abemaciclib in cell lines

 

 

 

Poster Presenters

Preeti Sharma, University of Illinois

T cell receptor and CAR-T engineering – T cell therapy

  • TCR Complex: Vbeta Cbeta P2A Valpha Calpha
  • CAR-T Aga2 HA scTCR/scFv c-myc
  • Directed elovution to isolate optimal TCR or CAR
  • Eng TCR and CARt cell therapy
  • Use of TCRs against pep/MHC allows targeting a n array of cancer antigens
  • TCRs are isolated from T cell clones
  • Conventional TCR identification method vs In Vitro TCR Eng directed evolution
  • T1 and RD1 TCRs drive activity against MART-1 in CD4+ T cells
  • CD8+
  • TCR engineering for Targeting glycosylated cancer antigens
  • Normal glycosylation vs Aberrant glycosylation
  • Engineering 237-CARs  libraries with conjugated (Tn-OTS8) against multiple human Tn-antigend
  • In vitro engineering: broaden specificity to multiple peptide backbone
  • CAR engineering collaborations with U Chicago, U Wash, UPenn, Copenhagen, Germany

 

Martin LaFleur, HMS

CRISPR- Cas9 Bone marrow stem cells for Cancer Immunotherapy

  • CHIME: CHimeric IMmune Editing system
  • sgRNA-Vex
  • CHIME can be used to KO genes in multiple immune lineages
  • identify T cell intrinsic effects in the LCMV model Spleen-depleted, Spleen enhanced
  • Loss of Ptpn2 enhances CD8+ T cell responses to LCMV and Tumors
  • Ptpn2 deletion in the immune system enhanced tumor immunity
  • CHIME enables in vivo screening

 

 

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Image Source:Koch Institute

LIVE – OCTOBER 17 – DAY 2- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium

Koch Institute Immune Engineering Symposium 2017

http://kochinstituteevents.cvent.com/events/koch-institute-immune-engineering-symposium-2017/agenda-64e5d3f55b964ff2a0643bd320b8e60d.aspx

Image Source: Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Aviva Lev-Ari, PhD, RN will be in attendance covering the event in REAL TIME

@pharma_BI

@AVIVA1950

#IESYMPOSIUM

@KOCHINSTITUTE

  • The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The Immune System and Therapeutics (Series D: BioMedicine & Immunology) Kindle Edition – on Amazon.com since September 4, 2017

https://www.amazon.com/dp/B075CXHY1B

SYMPOSIUM SCHEDULE

OCTOBER 17 – DAY 2

8:30 – 9:45 Session V
Moderator: Stefani Spranger | MIT, Koch Institute

K. Christopher Garcia – Stanford University
Exploiting T Cell and Cytokine Receptor Structure and Mechanism to Develop New Immunotherapeutic Strategies

  • T Cell Receptor, peptide-MHC, 10 to the power of 10 is combinatorics – Library for selection to determine enrichment possibilities
  • Ligand identification for orphan TCRs
  1. Industrializing process
  2. use pMHC
  • IL-2 – Receptor Signaling Complex
  • Effector cells (NK, T)
  • Engineered  T Cell – Tunable expansion, ligand-Receptor interface
  • Randomize IL-2RBeta interface: Orthogonal receptor vs wild type
  • In Vivo adoptive transfer model: to quantify orthogonality ratio
  • CD4, CD8, Treg,C57BL/6J
  • Ligand discovery
  • Orthogonal IL-2

Stefani Spranger – MIT, Koch Institute
Batf3-DC as Mediators of the T Cell-Inflamed Tumor Microenvironment

  • Melanoma – solid cancer and other types, Immune inhibitory regulatory pathway patient with Immune response present
  • T cell-inflamed Tumor vs Non-T cell-inflamed Tumor
  • identify oncogenic pathways differentially activated between T cell-inflamed and non-Tcell-inflamed infiltration
  • If on Tumor:
  1. Braf/PTEN
  2. Braf/CAT
  3. Braf/PTEN/CAT
  • The role of T cell priming – lack of initial
  • Beta-catenin-expressing tumors fail to prime 2C TCR-transgenic T cells
  • Deficiency in number of CD8+ and CD103+ dendritic cells
  • CD103+ DC are essential for T cell Priming and T cell-inflammation #StefaniSpranger
  • Adoptive transfer of effector 2C T cells fails to control Beta-catenin+ tumors
  • Vaccination induced anti-gen specific T cell memory fails to control Beta-catenin+ tumors
  • What cell type in tumor microenvironment effect monilization of T cell
  • CD103+ Dendritic cellsare source chymokine
  • Recruitment of effector T cells: Reconstitution od Beta-catenin-expressing SIY+
  • Are Batf3-DC within the tumor required for the recruitment of effector T cells?
  • Tumor-residing Batf3-drive CD103+ DC are required for the recruitment of effector T cells
  • Gene spore for correlation with recturment of effector cells
  • T cell Priming – CD103+ DC are essential for effector T cells

George Georgiou – University of Texas at Austin
The Human Circulating Antibody Repertoire in Infection, Vaccination or Cancer

  • Serological Antibody Repertoire: in blood or in secretions
  • Antibody in serum – is difficult sequence identity
  • Serum IgG – 7-17 mg/ml if less immune deficient if more hyper globular
  • antibodies produced in long lived plasma cells in the bone marrow — experimentally inaccessible
  • Discovery of antibodies from the serological repertoire – not B cells
  • BM-PCs
  • Serum antibodies function via Fc effector mechanism – complement activation
  • Ig-SEQ – BCR-SEQ
  • Repertoire-wide computational modelling of antibody structures
  • En masse analysis & Mining of the Human Native Antibody Repertoire
  • hypervariable – High-Throughput Single B Cell VH:VL (or TCRalpha, beta) sequencing
  • EBOV Vaccinee Peak ASCs (day 8) mining: Neutralization
  • Features of the Serum Antibody Repertoire to Vaccine ANtigens:The Serum IgG Repertoire is Highly Polarized
  • Each bar represents a distinct antibody lineage
  • Serum IgG Repertoire becomes increasingly polarized with AGE >50 – may be predictive of tumor development process
  • Human Norovirus – explosive Diarreha, chromically infected – HuNoV BNAb Discovery – Takeda 214 bivalent Vaccine – Binding antibodies binding to avccine antigen VLP
  • HuNoV causes 800 death in the US per year of immune deficient
  • Influenza Trivalent Vaccine: Antibodies to hemaggiutinin: H1, H3, and B COmponenet
  • Abundant H1 +H3 Serum IgGs do not neutralize but confer Protection toInfluenza challenge with Live Virus #GeorgeGeorgiou
  • Non-Neutralizing Antibodies: The role of Complement in Protection

9:45 – 10:15 Break

10:15 – 11:30 Session VI
Moderator: K. Dane Wittrup | MIT, Koch Institute

Harvey Lodish – Whitehead Institute and Koch Institute
Engineered Erythrocytes Covalently Linked to Antigenic Peptides Can Protect Against Autoimmune Disease

  • Modified Red blood cells are microparticles for introducing therapeutics & diagnostics into the human body
  • Bool transfusion is widely used therapeutics
  • Covalently linking unique functional modalities to mouse or human red cells produced in cell culture:
  • PRODUCTION OF HUMAN RED BLOD CELLS EXPRESSING A FOREIN PROTEIN: CD34+ stem/progenitor cells that generates normal enucleated RBC.
  • PPAR-alpha and glucocorticoticoid receptor
  • Norman morphology: Sortase A is a bactrial transpeptidase that covalently links a “donor”
  • Engineering Normal Human RBC biotin-LPETG
  • Covelantely – Glycophorin A with camelid VHHs specific for Botulinum toxin A or B
  • Generation of immuno tolerance: SOruggable Mature RBCs: CRISPR mice expressing Kell-LPETG
  • Ovalbumin as Model Antigens:
  1. OBI B,
  2. OTI CD8 T cells
  3. OTII CD4 T cells
  4. OT-1
  5. OT-2
  • RBC induced peptides challenged and experiences apoptosis
  • Type I Diabetes in NOD mice
  • RBCs bearing InsB9-23 – prevented development of diabetes

Multiple sclerosis

  • MOG – Myelin Oligodend

Sai Reddy – ETH Zurich
Molecular Convergence Patterns in Antibody Responses Predict Antigen Exposure

  • Clonal diversity – estimating the size of antibody repertoire: 10 to power of 18 or 10 to 13
  • Clonal selection in antibody repertoire
  • Convergent selection in antibody repertoire
  • Convergent selection in TCR repertoire complex have restriction with MCH interactions
  • How molecular abundance of convergence predicts antigen exposure identify antigen-associated clusters #SaiReddy
  • molecular convergence 0 gene expression analysis, immunization scheme molecular bar coding to correct errors
  • Recoding antibody repertoire sequence space: Cross correlation reveals different clusters
  • Building a classifier model based on cluster frequency: Clones from immunized mice
  • epitope specificity is driving antibody repertoire response
  • deep learning,

K. Dane Wittrup – MIT, Koch Institute
Temporal Programming of Synergistic Innate and Adaptive Immunotherapy

  • Innate effector functions of anti-tumor antibodies
  • Innate & adaptive Immunotherapy
  • Innate mAb –>> tumor cell; adaptive CD8+ T cells
  • Chemokines Antigens
  • Cytokines Chemokines – back and forth innate Adaptive –> <— neutrophils impact
  • AIPV vaccine:
  • How anti-TAA mAbs helping T cell Immune response
  • Anti-TAA mAbs drive vaccinal T cell responses: NK cells
  • antibody drives T cells responses: alpha-TAA mAbs potentiate T cell therapies: ACT +MSA-IL-2 vs alphaPD-1 + vaccine
  • CD8+ T cells required for alpha TAA mAb efficacy- In absence of T cells Treatment does not work
  • Anti-TAA mAb +Fc/IL-2 induces intramural cytokine storm #KDaneWittrup
  • How to simplify and improve AIPV? Hypothesis: ALign dose schedule
  • Immune response to infection follwos a temporal progression: Innate … Adaptive
  • Antigenic material kill cells: Chemo, cell death Antigen presentation, T cell priming, T cell recirculation, Lymphocyte tumor infiltrate, TCR
  • IFN alpha 2 dys after mAb +Il-2: Curative: days post tumor injection
  • Necessary components: CD8+ T cells & DC, Macrophages,
  • Optimal IFNalpha coincides with max innate response vs Mature DCs after antigen loading #KDaneWittrup
  • Optimal timing od agent administration effect on Therapy Outcome: IL-2, IFNalpha, TAAmAb
  • Cytkine timing can be better than protein engineering #KDaneWittrup

11:30 – 1:00 Lunch Break

1:00 – 2:15 Session VII
Moderator: Michael Birnbaum | MIT, Koch Institute

Kai Wucherpfennig – Dana-Farber Cancer Institute
Discovery of Novel Targets for Cancer Immunotherapy

  • POSITIVE STRESS SIGNAL during malignant Transformation
  • NKG2G=D Receptor: MICA/B Results in Immune escape – Proteolytic cleavage  shedding of MICA/B present in serum, indication of tumor progression
  • Shed MICA vs Surface MICA/B – restore NK cell cytotoxicity and IFNgamma Production
  • Human NK cells express NKG2D and Fc Receptors
  • Synergistic NKG2D and CD16 signaling enhances NK cell cytootxicity: Control IgG vs Anti NKG2D
  • MICA Antibody induces Immunity Against Lung Metastases
  • NK cells are required to inhibit Growth of metastases: Anti-CD8beta,
  • Contribution to Therapeutic Efficacy: NKG2D and CD16 Receptors #KaiWucherpfennig
  • Strategy to analyze Pulmonary NK cells: Activation and expression
  • Single cell RNA-seq of lung NK cells Revealed higher infiltration of activated NK cells: Isotype vs 7C6-migG2a
  • Cytokines and Chemokines produce NK cells
  • MICA/B increaces NK
  •  Induction of Tumor cell Apoptosis
  • Xenotransplant Model with Human Melanoma Cel Line A2058
  • Lung metastasis, liver metastasis
  • Inhibition of human melanoma Metastases in NSG Mice Reconstitute with Human NK
  • Liver metastases are controlled by Myeloid Cells that include Kupffer cells

Michael Birnbaum – MIT, Koch Institute
An Unbiased Determination of pMHC Repertoires for Better Antigen Prediction

  • Vaccines TCR gene therapy adoptive T cel therapy
  • Tumor genone – Tumor pMHC repertoire = Tumor TCR repertoire T cell repertoire
  • Neoantigen vaccines as a personalized anti-cancer therapy
  • Tumor procurement – Target selection – personal vaccine production – vaccine administration
  • Prediction of neoantigen-MHC Binding due to polimorphism affecting recognition, rare in MHC Allells #Michael Birnbaum
  • Antigenicity – Chaperones HLA-DM sculp the peptide binding repertoire of MHC
  • Identification of loaded peptide ligands: pMHC mass spectroscopy of tissue
  • TCR recognition, pMHC yeast display: Cleave peptide-MHC linker, catalyze peptide exchange
  • HLA-DR4 library design and selection to enrich HLA-DM: Amino Acid vs Peptide position: Depleted vs Enriched – relative to expected for NNK codon
  •  6852 _ predicted to bind vs 220 Non-binding peptides
  • HLA polymorphism: repertoire differences caused by
  • Antigen – T cell-driven antigen discovery: engaging Innate and Adaptive Immune response
  • Sorting TIL and select: FOcus of T cell-driven antigen discovery
  • T cell-driven antigen discovery: TCR

Jennifer R. Cochran – Stanford University
Innate and Adaptive Integrin-targeted Combination Immunotherapy

  • alpa-TAA
  • Targeting Integrin = universal target involved in binding to several receptors: brest, lung, pancreatic, brain tumors arising by mutations – used as a handle for binding to agents
  • NOD201 Peptide-Fc Fusion: A Psudo Ab
  • Handle the therapeutics: NOD201 + alphaPD1
  • NOD201 effectively combines with alphaPD-L1, alphaCTLA-4, and alpha4-1BB/CD137
  • Corresponding monotherapies vs ComboTherapy invoking Innate and Adaptive Immune System
  • Microphages, CD8+ are critical vs CD4+ Neutrophils, NK cells, B cells #JenniferR. Cochran
  • Macrophages activation is critical – Day 4, 4 and 5
  • NOD201 + alphaPD1 combo increases M1 macrophages
  • Who are the best responders to PD1 – genes that are differentially expressed
  • NOD201 deives T cells reaponses through a “vaccinal” effect
  • CAncer Immune CYcle
  • Integrin – localization
  • Prelim NOD201 toxicity studies: no significant effects
  • Targeting multiple integrins vs antibodies RJ9 – minimal effect
  • NOD201 – manufacturability – NEW AGENT in Preclinical stage

2:15 – 2:45 Break

2:45 – 3:35 Session VIII
Moderator: Jianzhu Chen | MIT, Koch Institute

Jennifer Wargo – MD Anderson Cancer Center
Understanding Responses to Cancer Therapy: The Tissue is the Issue, but the Scoop is in the Poop

  • Optimize Targeted Treatment response
  • Translational research in patients on targeted therapy revealed molecular and immune mechanisms of response and resistance
  • Molecular mechanisms – T cell infiltrate after one week of therapy
  • Role of tumor stroma in mediating resistance to targeted therapy
  • Tumor microenvironment
  • Intra-tumoral bacteria identified in patients with Pancreatic Cancer
  • Translational research in patients on immune checkpoint blockade revealed molecualr and immune mechanism of response and resistance
  • Biomarkers not found
  • SYstemic Immunity and environment (temperature) on response to checkpoint blockade – what is the role?
  • Role of mIcrobiome in shaping response to checkpoint blockade in Melanoma
  • Microbime and GI Cancer
  • Diversity of the gut microbiome is associated with differential outcomes in the setting of stem cell transplant in AML
  • Oral and gut fecal microbiome in large cohort patient with metastatic melanoma undergoing systemic therapy
  • Repeat oral & gut AFTER chemo
  • WGSeq – Diversity of microbiome and response (responders vs non-responders to anti PD-1 – High diversity of microbiome have prolonged survival to PD-1 blockade
  • Anti tumor Immunity and composition of gut microbiome in patient on anti-PD-1 favorable AND higher survival #JenniferWargo
  • Enhance therapeutic responses in lang and renal carcinoma: If on antibiotic – poorer survival
  • sharing data important across institutions

Jianzhu Chen – MIT, Koch Institute
Modulating Macrophages in Cancer Immunotherapy

  • Humanized mouth vs de novo human cancer
  • B cell hyperplasia
  • double hit lymphoma
  • AML
  • Overexpression of Bcl-2 & Myc in B cells leads to double-hit lymphoma
  • antiCD52 – CLL
  • Spleen, Bone marrow, Brain
  • Microphages are required to kill Ab-bound lymphoma cells in vivo #JianzhuChen
  • COmbinatorial chemo-Immunotherapy works for solid tumors: treating breast cancer in humanized mice
  • Infiltration of monocytic cells in the bone marrow
  • Cyclophosphophamide-antibody synergy extending to solid tumor and different antibodies #JianzhuChen
  • Polarization of macrophages it is dosage-dependent M1 and M2
  • Antibiotic induces expression of M1 polarizing supresses development and function of tumor-associated macrophages (TAM)
  • Antibiotic inhibits melanoma growth by activating macrophages in vivo #JianzhuChen

 

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