Immunotherapy in Cancer: turning T cells against cancer

Transcription

1 Immunotherapy in Cancer: turning T cells against cancer Frederick L. Locke, MD Director, Immune Cell Therapy Program Department of Blood and Marrow Transplant Cellular Immunotherapy Moffitt Cancer Center

2 Disclosures Consultant: Cellular BioMedicine Group Scientific Advisory Board Member: Kite Pharma Other: Moffitt Cancer Center has received research funding from Kite pharma I will be discussing off-label uses of the following FDA approved medications: Tocilizumab

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4 Antigen may be processed and presented on MHC molecules, to be recognized by the T cell receptor (TCR) Neefjes et al Nature Reviews Immunology 11:823

5 Productive T cell response requires a second signal (co-stimulation) Pardoll, 2012, Nature Reviews Cancer.

6 Upon T cell activation, inhibitory receptors on the T cell surface are upregulated, turning off the immune response Pardoll, 2012, Nature Reviews Cancer.

7 Ipilimumab, a CTLA-4 blocking antibody, was FDA approved for Malignant Melanoma in 2011 Hodi et al, 2010, NEJM

8 FDA approved Immune Checkpoint Inhibitors Target Drug Indication CTLA-4 PD-1 PD-L1 Ipilimumab (Yervoy) Nivolumab (Opdivo) Pembrolizumab (Keytruda) Atezolizumab (Tecentriq) Melanoma, metastatic Melanoma, adjuvant stage III Melanoma, metastatic Melanoma, adjuvant stage III Renal Cell Carcinoma, advanced Urothelial Carcinoma, metastatic Head and Neck Squamous, recurrent or metastatic Hodgkin Lymphoma, refractory Melanoma, metastatic Non-small cell Lung, with PD-L1 expression Head and Neck Squamous, recurrent or metastatic Hodgkin Lymphoma, refractory Urothelial Carcinoma, metastatic Non-small cell Lung, metastatic

9 In Girl s Last Hope, Altered Immune Cells Beat Leukemia Dec. 9, 2012 New York Times

10 Chimeric Antigen Receptor (CAR) T cell therapy Autologous Cellular Immunotherapy T cells removed and engineered to express a chimeric antigen receptor (CAR) Reprogramed T cells recognize cancer cell targets CD19 targeted CARs are furthest in development

11 Barrett, Curr Opin Pediatr, 2014

12 Pivotal trials of CD19 CAR T cells Company Indication Population Expected FDA approval Kite r/r DLBCL Adults 3Q17 Kite r/r ALL Adults 2Q18 Kite r/r MCL Adults 2Q18 Novartis r/r ALL Pediatrics/AYA 3Q17 CD19 CARs will land FDA approval in

13 Significant Unmet Need in Refractory Aggressive NHL Axicabtagene ciloleucel is an autologous chimeric antigen receptor (CAR) T therapy with a CD3ζ/CD28-based signaling that recognizes and eliminates CD19-expressing cells (anti-cd19) NHL is the most common hematologic malignancy in the US 1 Outcomes in Refractory Aggressive NHL Are Poor - SCHOLAR-1 patient level meta-analysis of refractory NHL 2 ORR of 26% (CR of 8%, PR of 18%) Median OS of 6.6 months NHL, non-hodgkin lymphoma. 1. Howlader N, et al. SEER Cancer Statistics Review, Crump M, et al. J Clin Oncol. 2016;34:7516. Locke & Neelapu et al AACR 2017 #9986

14 ZUMA-1: Multicenter Trial of Axi-cel in Refractory Aggressive NHL Phase 1 Refractory DLBCL/PMBCL/TFL (cohort of n = 6) Phase 2 Cohort 1 Refractory DLBCL (n = 72) Cohort 2 Refractory PMBCL/TFL (n = 20) Primary end point Phase 2: Objective Response Rate (ORR) tested in the first 92 patients dosed a Key secondary end points DOR, OS, safety, levels of CAR T and cytokines a Type 1 error was controlled at the 1-sided level and split between the testing of cohort 1 and cohorts 1 and 2 combined with the exact binomial test comparing observed ORR to a hypothesized rate of 20%. ORR was also assessed in all patients dosed (mitt) and in all patients enrolled (ITT) ASCT, autologous stem cell transplant; axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; DLBCL, diffuse large B cell lymphoma; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance score; mab, monoclonal antibody; NHL, non-hodgkin lymphoma; OS, overall survival; PMBCL; primary mediastinal B-cell lymphoma; TFL, transformed follicular lymphoma. Locke & Neelapu et al AACR 2017 #9986

15 ZUMA-1: Patient Consort Diagram Patients not treated: SAE (n = 5) No measurable disease (n = 2) Product unavailable (n = 1) SAE (n = 2) Enrolled (n = 111) Conditioning Cy 500 mg/m 2 + Flu 30 mg/m 2 3 d Axi-cel CAR+ cells/kg (N = 101) 22 sites enrolled; 99% manufacturing success rate 91% of enrolled patients received axi-cel 17-day average turnaround time from apheresis to delivery to clinical site Axi-cel, axicabtagene ciloleucel; Cy, cyclophosphamide; Flu, fludarabine; SAE, serious adverse event. Locke & Neelapu et al AACR 2017 #9986 No bridging therapy allowed N = 92: primary analysis (ORR) N = 101: modified intent-totreat (mitt) Data cutoff: January 27, 2017 Median follow-up: 8.7 months

16 ZUMA-1: Met Primary Endpoint ORR (P <.0001) a in Combined Group Best Response Median follow-up of 8.7 months ZUMA-1 Phase 2 DLBCL TFL/PMBCL Combined ORR (%) CR (%) ORR (%) CR (%) ORR (%) CR (%) mitt b n = 77 n = 24 n = a Inferential testing when 92 axi-cel dosed patients had 6 mo of follow-up. ORR 82%, P< b mitt (modified intention-to-treat) set of all patients dosed with axi-cel. CR, complete response; DLBCL, diffuse large B cell lymphoma; ORR; objective response rate; PMBCL; primary mediastinal B-cell lymphoma; TFL, transformed follicular lymphoma. Locke & Neelapu et al AACR 2017 #9986

17 6-month OS Rate 80% in ZUMA-1 vs. 55% in SCHOLAR-1 Median OS (95% CI), mo ZUMA-1 NR (10.5-NR) SCHOLAR ( ) 1. Crump et al. ASCO NR, not reached; OS, overall survival. Locke & Neelapu et al AACR 2017 #9986

18 Duration of Responses At a Median Follow-Up of 8.7 Months ORR 8.2 (3.3-NR) CR NR (8.2-NR) PR 1.9 ( ) CR, complete response; NR, not reached; ORR, objective response rate. Locke & Neelapu et al AACR 2017 #9986

19 6-Month PFS Rates Were Consistent Across Key Covariates Median PFS: 5.9 months (95% CI, ) ASCT, autologous stem cell transplant; IPI, International Prognostic Index; LCI, lower 95% confidence interval; PFS, progression-free survival; UCI, upper 95% confidence interval. Locke & Neelapu et al AACR 2017 #9986

20 Ongoing Complete Remission From ZUMA-1 62-Year-Old Man With Refractory DLBCL Prior therapies R-CHOP R-GDP R-ICE R-lenalidomide Baseline Month 3 Month 12 DLBCL, diffuse large B cell lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-GDP, rituximab, gemcitabine, dexamethasone, and cisplatin; R-ICE, rituximab, ifosfamide, carboplatin, and etoposide; R-lenalidomide, rituximab plus lenalidomide. Locke & Neelapu et al AACR 2017 #9986

21 Anti-CD19 CAR T Cell Therapy: Promising Clinical Benefit With a Distinct Adverse Event Profile CRS and NEs are 2 potentially serious adverse events associated with CAR T cell therapy and have also been reported with bispecific antibody therapies Cytokine Release Syndrome Mediated by high levels of inflammatory cytokines, such as IL-6 1 Symptoms include fever, tachycardia, hypotension, and hypoxia 2 Symptoms Neurologic Events Events are associated with high CAR T cell levels and/or high cytokine levels 3,4 Symptoms include confusion, tremor, aphasia, encephalopathy, and seizures 1 CRS and NE are often managed with tocilizumab, an anti IL-6 receptor antagonist and/or corticosteroids for immunosuppression 2 CAR, chimeric antigen receptor; CRS, cytokine release syndrome; IL, interleukin; NE, neurologic events. 1. Lee, et al. Blood. 2014;124: Neelapu, et al. Blood. 2016;128(suppl; abstr):lba Kochenderfer JN, et al. J Clin Oncol Mar 14. [epub ahead of print]. 4. Turtle CJ, et al. J Clin Invest. 2016;126: Locke, et al. AACR 2017 #CT020

22 Summary of AEs AE, n (%) Interim Analysis (N = 62) Primary Analysis (N = 101) Grade 3 AE 59 (95) 95 (95) Grade 3 CRS 11 (18) 13 (13) Grade 3 NE 21 (34) 28 (28) Grade 5 AE 3 (3) a 3 (3) a CRS and NE were generally reversible - All CRS events resolved except 1 case of HLH and 1 case of cardiac arrest - All NE resolved except 1 grade 1 memory impairment 43% received tocilizumab, 27% received steroids No cases of cerebral edema No new axi-cel related grade 5 AEs a As previously reported, grade 5 AEs occurred in 3 patients. Axi-cel related, 2 (2%; HLH and cardiac arrest); axi-cel unrelated, 1 (1%; pulmonary embolism). AE, adverse event; axi-cel, axicabtagene ciloleucel; CRS, cytokine release syndrome; HLH, hemophagocytic lymphohistiocytosis; NE, neurologic event. Locke & Neelapu et al AACR 2017 #9986

23 CAR T Cell Levels Peaked Within 7-14 Days in Patients Treated With Axi-cel axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; LOD, limit of detection. Locke, et al. AACR 2017 #CT020

24 Expansion of CAR T Cells Was Associated With Objective Response and Grade 3 NE ORR NE CRS CAR AUC defined as cumulative levels of CAR+ cells/µl of blood over the first 28 days post axi-cel. P Values are calculated by Wilcoxon rank sum test. AUC, area under the curve; axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; NE, neurologic events; ORR, objective response rate. Locke, et al. AACR 2017 #CT020

25 CAR T cell and T cell receptor (TCR) therapies are both engineered autologous T cell therapies against tumor targets CAR T-cell TCR Therapy Targets cell surface molecules Does not require HLA match Kershaw et al, Clin Transl Immun, Can target any tumor specific antigen Requires HLA match

26 Tumor infiltrating T cells from a cervical cancer patient were found to be reactive against HPV-16 proteins Draper & Hinrichs, Clin Cancer Res. 2015

27 Anti HPV-16 TCR transduced T cells activate, secrete IFNgamma, and are cytotoxic against HPV Draper and Hinrichs, Clin Can Res, 2015.

28 Ongoing clinical trials are testing out TCR engineered autologous T cell therapy for solid tumors HPV-16 E6 HPV-16 E7 MAGE A3 NY-ESO-1 Clinicaltrials.gov

29 We always overestimate the change that will occur in the next two years and underestimate the change that will occur in the next ten. Don't let yourself be lulled into inaction. Bill Gates

30 Immunology Working Group Abate Daga, Daniel Antonia, Scott Chung, Christine H. Djeu, Julie Y. Linda Kelley Mulé, James J. Mullinax, John E. Pilon-Thomas, Shari A. Ruffell, Brian Sahebjam, Solmaz Sarnaik, Amod A. Soliman, Hatem H. Wei, Sheng Wright, Ken Acknowledgments + Immune Cell Therapy Service Almhanna, Khaldoun Anasetti, Claudio Brayer, Jason B. Chavez, Julio C. Creelan, Ben C. Davila, Marco L. Druta, Mihaela Kharfan-Dabaja, Mohamed A. Fernandez, Hugo Lancet, Jeffrey E. Nishihori, Taiga Pinilla Ibarz, Javier Shah, Bijal Sweet, Kendra L. NCI-K23 Award (Locke) NCI-Cancer Clinical Investigator Team Leadership Award (Locke) Kite Pharma Will Go Jeff Wiezorek Adrian Bot John Rossi Dustin Khiem Sattva Neelapu All investigators and study staff that participated on Zuma 1 Matt Scott Donna Evans Austin Lannon