Personalized medicine - cancer immunotherapy

Transcription

1 Personalized medicine - cancer immunotherapy Özcan Met, PhD Senior Staff Scientist, Cell Therapy Director Center for Cancer Immune Therapy Department of Hematology Department of Oncology University Hospital Herlev ozcan.met@regionh.dk

2 Center for Cancer Immune Therapy, Herlev Hospital (2006-) 128 patients...ccit has a focus on development of immunological treatment of cancer with a translational research profile......numerous clinical trials are carried out based on a direct translation of the discoveries from the laboratory... 2 Personalized medicine - cancer immunotherapy

3 The basics 3 Personalized medicine - cancer immunotherapy

4 The basics ~1891: William Coley noted rare events of spontaneous tumor regression often preceded by infectious episodes : Coley injected more than 1000 cancer patients with bacteria or bacterial products. 4 Personalized medicine - cancer immunotherapy

5 The basics "...Immune system kill and also induce changes in the tumor resulting in tumor escape and recurrence..." (epigenetic changes or Darwinian selection) 5 Personalized medicine - cancer immunotherapy

6 The basics Cancer immunotherapy seeks to mobilize the immune system for therapeutic benefit in cancer 6 Personalized medicine - cancer immunotherapy

7 The basics 7 Personalized medicine - cancer immunotherapy

8 The basics 8 Personalized medicine - cancer immunotherapy

9 The DC approach...tumors are replete with potential tumor associated antigens (TAAs), and they can become immunogenic when presented by DCs... Perforin Granzymes IFN-γ TNF-α TNF-β Fas 9 Personalized medicine - cancer immunotherapy

10 The DC approach...tumors are replete with potential tumor associated antigens (TAAs), and they can become immunogenic when presented by DCs... Perforin Granzymes IFN-γ TNF-α TNF-β Fas 10 Personalized medicine - cancer immunotherapy

11 The DC approach PBMCs from 20 patients and 10 healthy donors were stimulated with autologous DCs transfected with p53, survivin or htert mrna and tumor-specific T cells were subsequently analyzed by ELISPOT IFN-γ release assay High frequency of preexisting cellular response in breast cancer patients against p53, survivin and htert at the time point of primary diagnosis 11 Personalized medicine - cancer immunotherapy

12 The DC approach 12 Personalized medicine - cancer immunotherapy

13 The DC approach PHASE I CLINICAL TRIAL Evaluation of DCs transfected with p53, survivin and htert or survivin and htert mrna in patients with metastatic breast cancer or malignant melanoma 13 Personalized medicine - cancer immunotherapy

14 The DC approach PHASE I CLINICAL TRIAL Evaluation of DCs transfected with p53, survivin and htert or survivin and htert mrna in patients with metastatic breast cancer or malignant melanoma...tumor-specific immune response was detected in five out of nine tested patients - two of which had response after treatment......there was an indication of clinical benefit; i.e. minor prolonged survival Personalized medicine - cancer immunotherapy

15 The DC approach DC-BASED CLINICAL TRIALS Summary of 6 completed studies using dendritic cells for immunotherapy in patients with breast cancer, renal cancer, melanoma and prostate cancer patients were treated between Tumor-specific immune response was detected in almost all patients treated......there was an indication of clinical benefit; however, more knowledge is needed in order for DCs to be exploited as a therapeutic option Personalized medicine - cancer immunotherapy

16 The DC approach Poor understanding of how to induce strong and sustained T-cell mediated immune responses against tumors in humans 16 Personalized medicine - cancer immunotherapy

17 The DC approach Immunosuppressive tumor microenvironment 17 Personalized medicine - cancer immunotherapy

18 T-cell therapy Chakravarti et al Trends in Biotech Personalized medicine - cancer immunotherapy

19 T-cell therapy Chakravarti et al Trends in Biotech Personalized medicine - cancer immunotherapy

20 T-cell therapy...after two courses of ACT treatment consisting of non-myeloablative chemotherapy, TIL and high dose IL-2 therapy... Tran KQ et al J Immunother Personalized medicine - cancer immunotherapy

21 T-cell therapy 21 Personalized medicine - cancer immunotherapy

22 T-cell therapy Clinical Cancer Res patients 3-step treatment: HD chemotherapy, TIL infusion, IL-2 Intermediate dose IL-2 (Decrescendo-regimen*) 18 MIU/m 2 over 6 h, 12 h and 24 h 4.5 MIU/m 2 over 24 h for 3 days *Keilholz et al. J Clin Oncol Personalized medicine - cancer immunotherapy

23 T-cell therapy 23 Personalized medicine - cancer immunotherapy

24 T-cell therapy 24 Personalized medicine - cancer immunotherapy

25 T-cell therapy Clinical Cancer Res Personalized medicine - cancer immunotherapy

26 (MM1409): Phase III (168 pts): TIL + HD bolus IL-2 vs Ipilimumab Generate robust efficacy data T-cell therapy Approval of TIL therapy as standard treatment (MM1413): pilot study (12 pts): TIL + decrescendo IL-2 + IFN-α IFN-αimproves tumor reactivity? (MM1414): pilot study (12 pts): TIL + decrescendo IL-2 + Vem Immunosensitization by vemurafenib (BRAF mutation) (GY1508): pilot study (6 pts): TIL + decrescendo IL-2 TIL in ovarian cancer (GY1508): pilot study (6 pts): TIL + decrescendo IL-2 TIL in renal cell carcinoma 26 Personalized medicine - cancer immunotherapy

27 Future T cell therapy Chakravarti et al Trends in Biotech Personalized medicine - cancer immunotherapy

28 CAR T-cell therapy Chakravarti et al Trends in Biotech Personalized medicine - cancer immunotherapy

29 CAR T-cell therapy Fesnak et al Nat Rev Cancer Personalized medicine - cancer immunotherapy

30 CAR T-cell therapy Fesnak et al Nat Rev Cancer Personalized medicine - cancer immunotherapy

31 CAR T-cell therapy mrna transfection Viral vectors Transient Permanent 31 Personalized medicine - cancer immunotherapy

32 CAR T-cell therapy Fesnak et al Nat Rev Cancer Personalized medicine - cancer immunotherapy

33 CAR T-cell therapy Fesnak et al Nat Rev Cancer Personalized medicine - cancer immunotherapy

34 CAR T-cell therapy 34 Personalized medicine - cancer immunotherapy

35 CAR T-cell therapy Manufacturing time is generally 5-10 days Fesnak et al Nat Rev Cancer Personalized medicine - cancer immunotherapy

36 CAR T-cell therapy CD19 CAR T cells targeting B-ALL (acute lymphoblastic leukemia) ALL, characterized by the overproduction and accumulation of cancerous, immature white blood cells => lymphoblasts lymphoblasts are overproduced in the bone marrow and continuously multiply => damage/death by inhibiting the production of normal cells (red/white blood cells and platelets) in the bone marrow and spreading to other organs ALL is most common in childhood, with a peak incidence at 2 5 years of age Most B-cell malignancies (and normal B cells...) express CD19 Absent in other cell types 36 Personalized medicine - cancer immunotherapy

37 CAR T-cell therapy CD19 CAR T cells targeting B-ALL (acute lymphoblastic leukemia) ALL, characterized by the overproduction and accumulation of cancerous, immature white blood cells => lymphoblasts lymphoblasts are overproduced in the bone marrow and continuously multiply => damage/death by inhibiting the production of normal cells (red/white blood cells and platelets) in the bone marrow and spreading to other organs ALL is most common in childhood, with a peak incidence at 2 5 years of age Most B-cell malignancies (and normal B cells...) express CD19 Absent in other cell types 37 Personalized medicine - cancer immunotherapy

38 CAR T-cell therapy CD19 CAR T cells targeting B-ALL (acute lymphoblastic leukemia) 38 Personalized medicine - cancer immunotherapy

39 CAR T-cell therapy CD19 CAR T cells targeting B-ALL (acute lymphoblastic leukemia) Khalil et al Nat Rev Clin Onc Personalized medicine - cancer immunotherapy

40 CAR T-cell therapy CD19 CAR T cells targeting B-ALL (acute lympoblastic leukemia) CD19 CAR T cells % CR in heavily pretreated patients Results of a large (n=609) US-UK cooperate group study treated adults with ALL after first relapse* Median survival 24 weeks 5-year overall survival 7% *Fielding, A. K. et al. Blood 109, (2007) Khalil et al Nat Rev Clin Onc Personalized medicine - cancer immunotherapy

41 CAR T-cell therapy toxicity? 41 Personalized medicine - cancer immunotherapy

42 CAR T-cell therapy toxicity? B-cell aplasia Due to CD19-expression (on-target off-tumor) Manageable by immunoglobin transfer (counteract depletion of antibody-producing B cells Cytokine-release syndrome Fast tumor cell lysis -> high levels of cytokine release and macrophage activation syndrome Often very high fevers, rigors, nausea and diarrhea associated with high levels of IFN-g and IL-6 Manageable by anti-il-6r antibody Research focus on optimal timing of anti-il-6 treatment 42 Personalized medicine - cancer immunotherapy

43 Challenges with CAR Fesnak et al Nat Rev Cancer Personalized medicine - cancer immunotherapy

44 Manufacturing challenges 44 Personalized medicine - cancer immunotherapy

45 Challenges with CARs Heatmap indicating geographic locations of ongoing or completed trials testing CAR T cells Maus et al Clin Can Res Personalized medicine - cancer immunotherapy

46 COPenhagen CAR T cell study group (COPCART) CCIT Processing and production of CAR T cells Immune monitoring and research labs Development of CARs POST (Paediatric Oncology and Stem Cell Transplantation, Righospitalet) Allogeneic HSCT Phase 1-2 trial unit Establishment of facilities for manufacturing of clinical grade CAR T cells Conduction of clinical trials with CD19 CAR T cell treatment in high risk CD19+ hematologic malignancies Develop Refractory predictive CD19+ markers ALL that allow early intervention in regards to toxicities related to CAR T cell therapy Patients referred for HSCT for which no matched donor is available patients with disease progression at the time point of planned HSCT Development of a fast-through-put method for testing of new CAR patients relapsing after HSCT T cells mrna transfection 46 Personalized medicine - cancer immunotherapy

47 Thank you!...there are few instances in drug development where there is no question that the therapy works Personalized medicine - cancer immunotherapy