Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Anti-Cancer Drug Discovery @ LPBI Group’s Research Biotech Businesses

Curator: Aviva Lev-Ari, PhD, RN

Part One: 

Anti-Cancer MATERIALS TO BE REVIEWED by Scientist Candidates for the Anti-Cancer Indication

Part Two: 

2.0   Immune System Stimulants

2.1   New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN), UC, Berkeley

2.2  Basic Research in Immune Oncology and Molecular Genomics: Methods to Stimulate Immunity by Alteration of Tumor Antigens, MGH

2.3   T Cells Receptor Like (TCRL) Antibodies – Technion, Israel

Part Three: 

Anti-Cancer – Four Drug Classes of Immune-Oncology Molecules in Development, including CAR-T

 

Part One: 

Anti-Cancer MATERIALS TO BE REVIEWED by Scientist Candidates for the

Anti-Cancer Indication

 

• Potential involvement in Drug Discovery on Anti-Cancer – CAR–T and TCRL in a newly under formation Biotech Start up as Scientist I,II,III or Project R&D Management

http://pharmaceuticalintelligence.com/gama-delta-epsilon-gde-is-a-global-holding-company-absorbing-lpbi/subsidiary-5-joint-ventures-for-ip-development-jvip/drug-discovery-with-3d-bioprinting/anti-cancer-car-t/

 

Start up will have employment opportunity for Scientist I,II,III and Project R&D Management positions per experience pending Funding secured to finance the Drug Discovery projects for the Three Indication, as above

Anti-Cancer MATERIALS TO BE REVIEWED by Scientist Candidates

For the Anti-Cancer Indication – Scientist Candidates will review the following links:

 

• Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

• Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

• Genomics Orientations for Personalized Medicine, on Amazon since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

• Series C: e-Books on Cancer & Oncology

Volume 2: Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery

• Next-generation Universal Cell Immunotherapy startup Adicet Bio, Menlo Park, CA is launched with $51M Funding by OrbiMed

Reporter: Aviva Lev-Ari, PhD, RN

• Pull at Cancer’s Levers 

Curator: Larry H. Bernstein, MD, FCAP

• Dr. David Orange-Webb Presentation to LPBI Group’s Team – April 8, 2016

  https://docs.google.com/presentation/d/1AKyBcHWlWdVE1JEVJn27XXpHCnXBKndzPZ6o6fJz5Mk/edit?pref=2&pli=1#slide=id.g10f889dcef_2_99

• Oncolytic Viruses in Cancer Therapy @ CHI’s PreClinical Congress, June 14, 2016 Westin Boston Waterfront, Boston

Reporter: Aviva Lev-Ari, PhD, RN

• Oncolytic Virus Immuno-Therapy: New Approach for a New Class of Immunotherapy Drugs

Curator: Larry H. Bernstein, MD, FCAP

• Real Time Coverage and eProceedings of 2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

Curator of Reported Contents: Aviva Lev-Ari, PhD, RN

• Pancreatic Cancer: Articles of Note @PharmaceuticalIntelligence.com

Part Two

2.0 Immune System Stimulants

• Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

• Immune System in Perspective

Curator: Larry H. Bernstein, MD, FCAP

• Three Methods for Design of a Novel Immune Therapy for Cancer: Conceptual Foundation for Development of a Novel Mechanism of Action for a Combination Therapy of Biologics

Curator:  Aviva Lev-Ari, PhD, RN

• Issues Need to be Resolved With Immuno-Modulatory Therapies: NK cells, mAbs, and adoptive T cells

Curator: Stephen J. Williams, PhD

• Cancer Research Institute, NYC, 6/23 – 6/24/2016: Will combination of adoptive t-cell therapy and anti-checkpoint inhibitor therapies be the next wave?

Reporter: Aviva Lev-Ari, PhD, RN

• From the Walter and Eliza Hall Institute of Medical Research: Hobbit and Blimp1 May Be Needed for Local Tissue Immune Response

Reporter: Stephen J Williams, PhD

• Targeting KRAS Mutations In Pancreatic Tumours

Curator: David Orchard-Webb, PhD

• Progress in the Design, Testing, and Approval of Immuno-therapeutic Reagents: Target the Most Promising Cancer Antigens  – NCI Pilot Project for the Acceleration of Translational Research

Reporter: Aviva Lev-Ari, PhD, RN

• The Value of Prediction for Response to Immunotherapies: Genomic Approaches for the Advancement of Neo-Antigen Understanding in Immunotherapy

Reporter: Aviva Lev-Ari, PhD, RN

 

2.1   New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN), UC, Berkeley

 

• New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN): Shrink Tumors and bolster Vaccines, re-arm the Immune System’s Natural Killer Cells, which attack Cancer Cells and Virus-infected Cells

Reporter: Aviva Lev-Ari, PhD, RN

• Adoptive NK T-Cells in Cancer Therapy

Curator: Larry H. Bernstein, MD, FCAP

• Novel molecules VY-OZ and VY-X demonstrate enhancement of killing capacity for cytotoxic lymphocytes by T-cells and natural killer cells (NK-cells) – products delivering: gene modification increasing in vivo and ex vivo immune response @Vycellix, Sarasota, FL

Reporter: Aviva Lev-Ari, PhD, RN

• CD-4 Therapy for Solid Tumors

Curator: Larry H. Bernstein, MD, FCAP

 

2.2  Basic Research in Immune Oncology and Molecular Genomics: Methods to Stimulate Immunity by Alteration of Tumor Antigens, MGH

• Basic Research in Immune Oncology and Molecular Genomics: Methods to Stimulate Immunity by Alteration of Tumor Antigens

Reporter: Aviva Lev-Ari, PhD, RN

 

• http://cancerres.aacrjournals.org/content/74/19_Supplement/2893.abstract

 

• http://conference.ncri.org.uk/abstracts/2013/abstracts/B63.htm

2.3   T Cells Receptor Like (TCRL) Antibodies: Major Considerations, Technion, Israel

1. Melanoma cells present high levels of HLA-A2-tyrosinase in association with instability and aberrant intracellular processing of tyrosinase.

Co-localization experiments revealed that, in cell lines presenting low levels of HLA-A2-Tyr ((369-377)) complexes, tyrosinase co-localizes with LAMP-1, a melanosome marker, whereas in cell lines presenting high HLA-A2-Tyr((369-377)) levels, tyrosinase localizes to the endoplasmic reticulum. We also observed differences in tyrosinase molecular weight and glycosylation composition as well as major differences in protein stability (t(1/2) ). By stabilizing the tyrosinase protein, we observed a dramatic decrease in HLA-A2-tyrosinase presentation.

Eur J Immunol. 2012 Apr; 42(4):842-50.    http://dx.doi.org:/10.1002/eji.201141511

 

2. Tumour and virus-infected cells are recognised by CD8+ cytotoxic T cells that, in response, are activated to eliminate these cells.

In order to be activated, the clonotypic T-cell receptor (TCR) needs to encounter a specific peptide antigen presented by the membrane surface major histocompatibility complex (MHC) molecule. Cells that have undergone malignant transformation or viral infection present peptides derived from tumour-associated antigens or viral proteins on their MHC class I molecules. Therefore, disease-specific MHC-peptide complexes are desirable targets for immunotherapeutic approaches. One such approach transforms the unique fine specificity but low intrinsic affinity of TCRs to MHC-peptide complexes into high-affinity soluble antibody molecules endowed with a TCR-like specificity towards tumour or viral epitopes. These antibodies, termed TCR-like antibodies, are being developed as a new class of immunotherapeutics that can target tumour and virus-infected cells and mediate their specific killing. In addition to their therapeutic capabilities, TCR-like antibodies are being developed as diagnostic reagents for cancer and infectious diseases, and serve as valuable research tools for studying MHC class I antigen presentation.
Expert Rev Mol Med. 2012 Feb 24; 14:e6.    http://dx.doi.org:/10.1017/erm.2012.2

 

3. we propose and demonstrate a generic electrical-to-biological transducer comprising a two-state electronic antigen and a chimeric cell receptor engineered to bind the antigen exclusively in its “on” state. T-cells expressing these receptors remain inactivated with the antigen in its “off” state. Switching the antigen to its “on” state by an electrical signal leads to its recognition by the T-cells and correspondingly to cell activation.

Nano Lett. 2011 Nov 9; 11(11):4997-5001. http://dx.doi.org:/10.1021/nl202971r

 

4. antigen targeting via the human DCIR receptor allows activation of specific CD8(+) T-cell immunityEnhanced specific CD8(+) T-cell responses were observed when an antigen was delivered to the DCs via DCIR, compared with those induced by a free antigen, or antigen conjugated to a control monoclonal antibody or delivered via DC-SIGN, another lectin receptor. DCIR targeting also induced primary CD8(+) T-cell responses against self (MART-1) and viral (HIV gag) antigens. Addition of Toll-like receptor (TLR) 7/8 agonist enhanced DCIR-mediated cross-presentation as well as cross-priming2010 Sep 9; 116(10):1685-97.  http://dx.doi.org:/10.1182/blood-2010-01-264960

 

5. unexpected high level presentation of tyrosinase-HLA-A2 Complexes revealed by peptide-specific, MHC-restricted, TCR-like antibodies.

J Immunol. 2009 May 15; 182(10):6328-41.    http://dx.doi.org:/10.4049/jimmunol.0801898

 

6. Heterogeneous cell populations form an interconnected network that determine their collective output

Despite the large number of subpopulations compositions, we were able to computationally extract a simple set of subpopulation-based rules that accurately predict the degree of reactivity. This raised the conjecture of whether one could control reactivity of TILs by manipulating their subpopulation composition. Remarkably, by rationally enriching and depleting selected subsets of subpopulations, we were able to restore anti-tumor reactivity to nonreactive TILs

Mol Syst Biol. 2009; 5:265.    http://dx.doi.org:/10.1038/msb.2009.15

 

7. the human skin displays three DC subsets, two of which, i.e., CD14(+) DCs and LCs, display functional specializations, the preferential activation of humoral and cellular immunity

Immunity. 2008 Sep 19; 29(3):497-510.    http://dx.doi.org:10.1016/j.immuni.2008.07.013

 

8. many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents;

This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations.         Oncogene. 2007 May 28;26(25):3714-33.

 

9. Dr. David Orchard-Webb Presentation to LPBI Group’s Team – April 8, 2016

• https://docs.google.com/presentation/d/1AKyBcHWlWdVE1JEVJn27XXpHCnXBKndzPZ6o6fJz5Mk/edit?pref=2&pli=1#slide=id.g10f889dcef_2_99

Part Three

Anti-Cancer – Four Drug Classes of Immune-Oncology

Molecules in Development, including CAR-T

 

Curator: Stephen J Williams, PhD

Phase in Development	Checkpoint Inhibitors Drug/Pharma	Co-Stimulatory Agents Drug/Pharma	Immunomodulators Drug/Pharma	5th generation CAR Signaling Pharma/Partners Listed as Drug (Target/disease indication)
Pre-Clinical	REGN2810/Regeneron PD-1/Agenus Anti-Lag3/Tesaro, AnaptyBio IMP701/Prima BioMed LAG3/Agenus, Incyte Lag3/Merck Anti-TIM3/Bristol Anti-TIM3/Tesaro, AnaptyBio Anti-TIM3/Agenus	OX40/Amgen GITR/Bristol GITR/Pfizer FPA154/Five Prime Anti-GITR/TG Therapeutics Anti-GITR/Incyte	CTLA4/Agenus IDO1/Pfizer,iTEOS F001287/Bristol,Flexus IMA942/Roche VIBR/Pfizer	Kite Pharma/Amgen Multiple targets/ hematologic & solid tumors Bellicum Pharma BPX-401 (CD19/leukemia) BPX-601 (PSCA/prostate) BPX-701 (PRAME/melanoma Cellectis/PfizerCornel/Ohio State UCART123 (CD123/AML) UCARTCS1 (CD38/multiple myeloma) UCART 38 (CD38 /multiple myeloma) UCART 22 ( CD22/ALL) Juno Therapeutics/Cellgene MUC116 (IL12/ovarian) ROR1 (ROR1/B-ALL) Univ. of Penna/Novartis CAR-T hPSMA (PSMA/prostate)
Phase I	BMS986016/Bristol	Urelumab/ BristolMyers MEDI-0562/ AstraZeneca RG7888/Roche OX40/Agonox OX40/GSK MK-4166/Merck SEA-CD40/Seattle Genetics CD40/Roche	Anti-CEA Il2v/Roche FPA008/Bristol, Five Prime LY3022855/Lilly AMG820/Amgen ARRY382/Array, Celgene	Ziopharm/Intrexon/ MD Anderson CD19 (CD19/B-ALL) Kite Pharma/Amgen KTE-C19 (ZUMA-3/Adult ALL) KTE-C19 (ZUMA-4/pediatric ALL) EGFRvII (EGFR/glioblastoma) Bluebird Bio/Cellgene/Baylor bb2121 (BCMA/B-ALL) Juno Therapeutics/Cellgene JCAR017 (CD19/leukemias) JCAR014 (CD19/NHLymphoma)
Phase I/II	MEDI0680/AstraZenec	PF-05082566/Pfizer Varilumab/Celldex, Bristol-Myers	NKG2A/Innate,AstraZen. dCellVax/BioMatrix APN301/Apeiron, MerckKGA	Juno Therapeutics/Cellgene JCAR015 (CD19/ALL) JTCR016 (WT-1/AML,CML)
Phase II	Pidlizumab/Medivation Avelumab/Pfizer, MerckKGa		Lirilumab/BMY/Innate Epacadostat/Incyte, Merck GDC-0919/NewLinkGenetics, Roche TG4010/Transgene S.A. Ontak/Esai, Lilly, Teva Denenicokin/Bristol, NovoNordisk PLX3397/Plexikon, Merck MCS110/Novartis JNJ40346527/JNJ T-Vec/Amgen Emactuzumab/Roche	Univ. of Penna/Novartis CTL019 (CD19/leukemia) Kite Pharma/Amgen KTE-C19 (ZUMA-1/leukemia) KTE-C19 (ZUMA-2/mantle cell leukemia)
Phase III	Duvalumab/AstraZenca Atezolizumab/Roche		Tremelimumab/AstraZeneca
Approved	Opdivo/Bristol-Myers Keytruda/Merck		Yervoy/Bristol-Myers

 Please see the following table In Word (as an 11 x 17 format table) below:

Table JPM2016 ImmuneTherapy in Development