Immunotherapy II: Engineered Cell Therapy March 17-18, 2015 New York, NY
Immunotherapy II: Engineered Cell Therapy Moderator: Mike Rice, MS, MBA, Senior Consultant, Defined Health Panelists: Renier J. Brentjens, MD, PhD, Director, Cellular Therapeutics, Associate Attending Physician, Dept of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center Thomas J. Farrell, CEO, Bellicum Pharmaceuticals Prof. Dolores J. Schendel, PhD, Chief Scientific Officer, Medigene Gaurav Shah, MD, Global Clinical Program Head, (CART/CTL019, Adoptive T-cell therapies), Novartis Pharmaceuticals Cassian Yee, MD, Professor, Dept of Melanoma Medical Oncology, Professor, Dept of Immunology, Director, Solid Tumor Cell Therapy, MD Anderson Cancer Center 2
Old News: Immuno-Oncology Has Become the Hottest Space in Cancer FierceBiotech, Citibank, Science Page 3
Gene and Cell Therapies Are Important Components of the Cancer Immunotherapy Tool Kit T-Cell Receptors (TCRs) Tumor Infiltrating Lymphocytes (TILs) Chimeric Antigen Receptors (CARs) http://www.intechopen.com/books/melanoma-in-the-clinic-diagnosis-management-and-complications-of-malignancy/adoptive-t-cell-therapy-of-melanoma-promises-and-challenges Page 4
25 Years After the First Publication of Genetic Redirection of T cells, Robust Clinical Efficacy of CAR19 T-Cells Demonstrated in R/R ALL Patients with high-risk B-cell malignancies represent the first beneficiaries of CD19 Targeted CAR T-Cells 2013: investigators from MSKCC, the UPenn, and the NCI simultaneously reported complete remission (CR) rates ranging from 71-85% in a total of 23 pediatric and 17 adult patients with R/R ALL, using slightly different versions of CD19-targeted CAR T cells. 2014: The same group of investigators published the updated results from respective phase I clinical trials, confirming the robust response rates and durability of response in a larger group of patients. On July 1, 2014, the FDA granted breakthrough therapy designation to Upenn/Novartis CTL019, the anti- CD19 chimeric antigen receptor T-cell therapy >100 patients treated and >30 active CAR19 T-Cell clinical trials recruiting A handful of trials are targeting non-cd19 hematological and solid malignancies and represent the next step to develop CAR T-cell therapy beyond B-cell malignancies. 2014 ASH Education Book Page 5
Clinical PoC Triggers Flurry of Investments into CAR-Ts A growing number of biotechs are now well-financed to translate CAR-Ts into commercial products: CAR-Ts: Juno Therapeutics, bluebird bio, Kite Pharma, Cellectis S.A., Bellicum, Cardio3 and Autolus Pharma has entered the space, both through traditional risk-sharing partnerships with biotech (e.g. Pfizer-Cellectis) and direct academic collaborations (e.g. Novartis-UPenn, Amgen/Kite). FierceBiotech, company press releases Page 6
Although Analysts Coverage Just Beginning CAR T-Cells Anticipating Rapid Growth in ALL and NHL Key industry CAR-T Pipeline Projected CAR19 T-Cell WW Market (Limited Products/Indications Currently Covered) $2,500 WW Sales ($M) $2,000 $1,500 $1,000 KTE-C19 (DLBCL, KITE) CTL019 (ALL, Novartis) Blincyto (ALL, Amgen) $500 $0 2012 2013 2014 2015 2016 2017 2018 2019 2020 EvaluatePharma Page 7
And Investments into Alternative T-Cell Approaches TCR and non-cell based monoclonal TCRs: Adaptimmune, Immunocore and Medigene TILs (Lion Biotechnologies) and universal donor T-cells (Atara). FierceBiotech, company press releases, company websites Page 8
However, Adoptive T-Cell Therapy Approaches Are Still Evolving as More is Learned About the Potential of this Immunotherapy Approach Developments in chimeric antigen receptor (CAR) structure have led to several design generations, which primarily differ in their cytoplasmic signalling domains. First-generation CARs contained a single cytoplasmic signalling domain that was derived from either CD3ζ or FcεRIγ. Firstgeneration CARs lacked Co-stimulatory signals. Second-generation CARs were developed that contained a co-stimulatory domain (CD28, CD27, CD134, CD137, CD244, ICOS or LCK. Third-generation receptors have an additional signalling domain, represented in the figure by CD137. Although not fully characterized, the inclusion of additional cytoplasmic domains could trigger several molecular signalling pathways as shown, leading to the amplification of the response against tumor antigen. Nature Reviews Cancer 532 AUGUST 2013 VOLUME 13 Page 9
At Least 7 Features Necessary To Optimize Adoptive T-Cell Therapies Nature Reviews Cancer 532 AUGUST 2013 VOLUME 13 Page 10
Progress on the Safety, Tolerability and Versatility on CAR T-Cell Immunotherapies May Enable Broader Application Gene-engineered T cells are directed towards tumorassociated antigens (TAAs) and so they have a reasonable level of specificity for tumors However, considerable toxicity can sometimes occur if the TAA is expressed on some vital organs, or if the T cell responses against the tumor are so great that large amounts of cytokine are secreted in a process termed cytokine storm Therefore, various strategies are being pursued to enhance the safety of gene-engineered T cells, which include methods for eliminating them or for switching antigen receptor expression off following transfer Other potential sources of toxicity include the mispairing of transgene T cell receptor (TCR) chains with endogenous TCR chains to produce self-reactive T cells, and the malignant transformation of the genemodified T cells themselves owing to dysregulation of proto-oncogenes by genomic integration of genetic vectors There are various approaches that aim to enhance the safety of adoptive cell transfer using gene-engineered T cells (see the table) Strategies for Increasing Safety of CARs Page 11
Most Pharma Have a Major Stake in Antibody and Vaccine Approaches, But Increasing in Cell and Gene Therapies Clinical Stage Immuno- Oncology Assets NVS ROC LLY AZN GSK CELG TAK AMG BMS SNY ABV MRK PFE BAY JNJ MRK KGaA VRX Cytokines I I Checkpoint/ Costims III II III I M M I III II Vaccines III II I I I II M Oncolytic Viruses Adoptive Cell Therapy Pre Reg II I Pre Pre TCR/BiTes I I I/II M I Other Immunomodulatory I II II Adis R&D Insight, Defined Health;; NVS, Novartis; ROC, Roche/Genentech; LLY, Eli Lilly; AZN, AstraZenca/MedImmune; GSK, GlaxoSmithKline; CELG, Celgene; TAK, Takeda; AMG, Amgen; BMS, Bristol-Myers Squibb; SNY, Sanofi; ABV, Abbvie; MRK Merck; PFE, Pfizer*; BAY, Bayer; JNJ, Johnson & Johnson; MRK KGaA, Merck KGaA; VRX, Valeant Page 12
2013-2015 Highest Deal Values for Gene/Cell Therapy Platform Companies Alliance License / Acq Class Phase Upfront ($MM) Total ($MM) Pfizer/ Cellectis - T cell therapy Research project 80 2,855 Servier/ Cellectis In-licensed CD19 cell therapy Pre-clinical - 840 GSK/ Adaptimmune In-licensed Anti-NY-ESO-1 T cell therapy Phase II - 350 Intrexon/ MDACC/ U. Minn In-licensed Chimeric antigen receptor (CAR) T cell therapy Research project - 110 ZIOPHARM Oncology/ MDACC/ U. Minn In-licensed Chimeric antigen receptor (CAR) T cell therapy Research project - 110 Amgen/Kite Pharma In-licensed Chimeric antigen receptor (CAR) T cell therapy Research project - - Celgene/ bluebird bio In-licensed Anti-cancer agent Research project - - Juno Therapeutics/ Opus Bio In-licensed CD22 cell therapy Phase I - - Atara Biotherapeutics/ MSKCC In-licensed Anti-cancer agent Phase II - - Ascend Bio/ Transgene In-licensed Oncolytic virus Phase II - - EvaluatePharma Oxford BioMedica/ Novartis Out-licensed technology T cell therapy Phase II - - Page 13
2013-2015 IPOs Gene/Cell Therapy Platform Companies Company Class Highest Phase IPO Date Amount Raised by IPO ($MM) Atara Biotherapeutics Cell therapy Phase II 10/16/2014 63.3 Bellicum Pharmaceuticals T cell therapy/anti-gd2 cell therapy/mesenchymal stem cell therapy Phase II 12/18/2014 160.6 Bio-Matrix Scientific Group Cell therapy Preclinical 8/14/2014 - Cardio3 BioSciences T cell therapy Phase I 6/20/2013 30.0 Juno Therapeutics Kite Pharma Chimeric antigen receptor (CAR) T cell therapy/anti-cd19 cell therapy/cd22 cell therapy Dendritic cell therapy/car T cell therapy/anti-ny- ESO-1 T cell therapy Phase II 12/19/2014 304.2 Phase II 6/20/2014 146.6 Lion Biotechnologies Cell therapy Phase II 9/26/2013 - MabVax Therapeutics Holdings CAR T cell therapy Research 5/12/2014 - TxCell Cell therapy Research 4/11/2014 22.4 Vascular Biogenics Gene therapy Phase II 10/1/2014 46.0 EvaluatePharma Page 14
Venture Financing 2013-2015: Cell Therapy Platform Companies Company Class Most Recent Financing Round Financing Date Investment ($MM) Atara Biotherapeutics Cell therapy Series B 1/10/14 13.5 Bellicum Pharmaceuticals T cell therapy/anti-gd2 cell therapy/mesenchymal stem cell therapy Series C 8/27/2014 55 Cardio3 BioSciences T cell therapy Private Investment in Public Equity (PIPE) 12/16/2013 3.4 Juno Therapeutics CAR T cell therapy/anti-cd19 cell therapy/cd22 cell therapy Series B 8/5/2014 134 Kite Pharma CAR T cell therapy/anti-ny-eso-1 T cell therapy Series A 5/15/2013 20 Lion Biotechnologies MabVax Therapeutics Holdings Cellectis TIL Cell therapy Private Investment in Public Equity (PIPE) 11/6/2013 23.3 CAR T cell therapy Series D 7/9/2014 3 IL-2/Anti-CD19/Anti-BCMA/Anti-CD38/Anti-EgfrVIII CAR T cell therap Private Investment in Public Equity (PIPE) 3/31/2014 28 Sorrento Therapeutics NK cell therapy PIPE 12/15/2014 - Adaptimmune Anti-NY-ESO-1 T cell therapy Series A 9/25/2014 104 Cell Medica Stem cell therapy Series B 11/25/2014 80.4 Conkwest NK cell therapy, HER2 (ErbB-2) inhibitor, CD20 inhibitor, Undisclosed 12/24/2014 50 EvaluatePharma Page 15
Immunotherapy II: Engineered Cell Therapy Moderator: Mike Rice, MS, MBA, Senior Consultant, Defined Health Panelists: Renier J. Brentjens, MD, PhD, Director, Cellular Therapeutics, Associate Attending Physician, Dept of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center Thomas J. Farrell, CEO, Bellicum Pharmaceuticals Prof. Dolores J. Schendel, PhD, Chief Scientific Officer, Medigene Gaurav Shah, MD, Global Clinical Program Head, (CART/CTL019, Adoptive T-cell therapies), Novartis Pharmaceuticals Cassian Yee, MD, Professor, Dept of Melanoma Medical Oncology, Professor, Dept of Immunology, Director, Solid Tumor Cell Therapy, MD Anderson Cancer Center 16