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
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:
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
Reporter: Aviva Lev-Ari, PhD, RN
Curator: Larry H. Bernstein, MD, FCAP
-
Dr. David Orange-Webb Presentation to LPBI Group’s Team – April 8, 2016
- Oncolytic Viruses in Cancer Therapy @ CHI’s PreClinical Congress, June 14, 2016 Westin Boston Waterfront, Boston
Reporter: Aviva Lev-Ari, PhD, RN
Curator: Larry H. Bernstein, MD, FCAP
Curator of Reported Contents: Aviva Lev-Ari, PhD, RN
Part Two
2.0 Immune System Stimulants
Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Curator: Larry H. Bernstein, MD, FCAP
Curator: Aviva Lev-Ari, PhD, RN
Curator: Stephen J. Williams, PhD
Reporter: Aviva Lev-Ari, PhD, RN
Reporter: Stephen J Williams, PhD
Curator: David Orchard-Webb, PhD
Reporter: Aviva Lev-Ari, PhD, RN
Reporter: Aviva Lev-Ari, PhD, RN
2.1 New Class of Immune System Stimulants: Cyclic Di-Nucleotides (CDN), UC, Berkeley
Reporter: Aviva Lev-Ari, PhD, RN
Curator: Larry H. Bernstein, MD, FCAP
Reporter: Aviva Lev-Ari, PhD, RN
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
Reporter: Aviva Lev-Ari, PhD, RN
2.3 T Cells Receptor Like (TCRL) Antibodies: Major Considerations, Technion, Israel
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Part Three
Anti-Cancer – Four Drug Classes of Immune-Oncology
Molecules in Development, including CAR-T
Curator: Stephen J Williams, PhD
Phase inDevelopment |
Checkpoint InhibitorsDrug/Pharma |
Co-Stimulatory AgentsDrug/Pharma |
ImmunomodulatorsDrug/Pharma |
5th generation CAR SignalingPharma/PartnersListed asDrug (Target/disease indication) |
Pre-Clinical |
REGN2810/RegeneronPD-1/AgenusAnti-Lag3/Tesaro, AnaptyBioIMP701/Prima BioMedLAG3/Agenus, IncyteLag3/MerckAnti-TIM3/BristolAnti-TIM3/Tesaro, AnaptyBioAnti-TIM3/Agenus |
OX40/AmgenGITR/BristolGITR/PfizerFPA154/Five PrimeAnti-GITR/TG TherapeuticsAnti-GITR/Incyte |
CTLA4/AgenusIDO1/Pfizer,iTEOSF001287/Bristol,FlexusIMA942/RocheVIBR/Pfizer |
Kite Pharma/AmgenMultiple targets/ hematologic & solid tumorsBellicum PharmaBPX-401 (CD19/leukemia)BPX-601 (PSCA/prostate)BPX-701 (PRAME/melanomaCellectis/PfizerCornel/Ohio StateUCART123 (CD123/AML)UCARTCS1 (CD38/multiple myeloma)UCART 38 (CD38 /multiple myeloma)UCART 22 ( CD22/ALL)Juno Therapeutics/CellgeneMUC116 (IL12/ovarian)ROR1 (ROR1/B-ALL)Univ. of Penna/NovartisCAR-T hPSMA (PSMA/prostate) |
Phase I |
BMS986016/Bristol |
Urelumab/ BristolMyersMEDI-0562/ AstraZenecaRG7888/RocheOX40/AgonoxOX40/GSKMK-4166/MerckSEA-CD40/Seattle GeneticsCD40/Roche |
Anti-CEA Il2v/RocheFPA008/Bristol, Five PrimeLY3022855/LillyAMG820/AmgenARRY382/Array, Celgene |
Ziopharm/Intrexon/ MD AndersonCD19 (CD19/B-ALL)Kite Pharma/AmgenKTE-C19 (ZUMA-3/Adult ALL)KTE-C19 (ZUMA-4/pediatric ALL)EGFRvII (EGFR/glioblastoma)Bluebird Bio/Cellgene/Baylorbb2121 (BCMA/B-ALL)Juno Therapeutics/CellgeneJCAR017 (CD19/leukemias)JCAR014 (CD19/NHLymphoma) |
Phase I/II |
MEDI0680/AstraZenec |
PF-05082566/PfizerVarilumab/Celldex, Bristol-Myers |
NKG2A/Innate,AstraZen.dCellVax/BioMatrixAPN301/Apeiron, MerckKGA |
Juno Therapeutics/CellgeneJCAR015 (CD19/ALL)JTCR016 (WT-1/AML,CML) |
Phase II |
Pidlizumab/MedivationAvelumab/Pfizer, MerckKGa |
Lirilumab/BMY/InnateEpacadostat/Incyte, MerckGDC-0919/NewLinkGenetics, RocheTG4010/Transgene S.A.Ontak/Esai, Lilly, TevaDenenicokin/Bristol, NovoNordiskPLX3397/Plexikon, MerckMCS110/NovartisJNJ40346527/JNJT-Vec/AmgenEmactuzumab/Roche |
Univ. of Penna/NovartisCTL019 (CD19/leukemia)Kite Pharma/AmgenKTE-C19 (ZUMA-1/leukemia)KTE-C19 (ZUMA-2/mantle cell leukemia) |
|
Phase III |
Duvalumab/AstraZencaAtezolizumab/Roche |
Tremelimumab/AstraZeneca |
||
Approved |
Opdivo/Bristol-MyersKeytruda/Merck |
Yervoy/Bristol-Myers |
Please see the following table In Word (as an 11 x 17 format table) below:
Table JPM2016 ImmuneTherapy in Development