Cell Therapies. John HaanenMD PhD

Transcription

1 Cell Therapies John HaanenMD PhD

2 My disclosures I have provided consultation, attended advisory boards, and/or provided lectures for: Pfizer, Bayer, MSD, BMS, IPSEN, Novartis, Roche/Genentech, Astra Zeneca/MedImmune, Seattle Genetics, Immunocore, Neon Therapeutics, Celsius Therapeutics, GadetaBV, for which NKI received honoraria Through my work NKI received grant support from BMS, MSD, Novartis and Neon Therapeutics

3 Tumor recognition of T cells is determined solely by the T cell receptor Reasons T cells do not kill cancer cell: Defective T cell repertoire Loss of antigen presentation Immune suppressive tumor micro-environment

4 Adoptivecelltherapyplatforms June, Riddell, Schumacher 2015 Science Trans Med

5 Tumor infiltrating lymphocytes: TIL therapy Steven A. Rosenberg Nature Reviews Clinical Oncology (2011) From: Restifoet al., Nat Rev Immunol2012

6 Goffet al., J ClinOncol 2016

7 Patient characteristics Goffet al., J ClinOncol 2016

8 Survival of patientsreceivingtil treatment Progression Free Survival Overall Survival Goffet al., J ClinOncol 2016

9 NMA TIL Response totil treatment NMA cGy TIL 24% of patientsdevelopeda CR, only1 of these progressed. Median FU 40.9 months Goffet al., J ClinOncol 2016

10 Lymphodepletion prior to T cell transfer is followed by immune reconstitution Rosenberg & Restifo Science 2015

11 14 mm 24 mm mm

12 Patient treated in the RCT with TIL after failure to pembrolizumab Prior totil 3 monthsaftertil

13 Clinical data N10TIL003 patient: CR at 12 weeks Prior to TIL 3 wks post TIL 8 wks post TIL 12 wks post TIL Biopsyat 7 weeks showednoviabletumor cells ongoingcr >6 years

14 Adoptiveimmunotherapyof cancer 1. Evidence that adoptive T cell therapy can do something useful 2. How can we determine how adoptive T cell therapies mediate their effect? 3. How can we generate more defined & more broadly applicable forms of adoptive T cell therapy?

15 Immunotherapy of melanoma: TIL therapy TIL are grown from melanoma tumors Rapid Expansion Infusion of TIL + IL-2 Patient pretreated with lymphodepleting chemotherapy

16 Immunotherapy of melanoma: TIL therapy TIL are grown from melanoma tumors Rapid Expansion A few million T cells 1x10 11 T cells

17 How does TIL therapy work? TIL are grown from melanoma tumors Rapid Expansion? Infusion of TIL + IL-2 Patient pretreated with lymphodepleting chemotherapy 1. Which (cytotoxic) T cells mediate cancer regression? 2. Could we specifically boost their numbers?

18 What do tumor-specific cytotoxic T cells detect on tumor cells? 1. Self antigens (to which tolerance is incomplete) 2. Neo-antigens, epitopes that are truly foreign

19 What do tumor-specific cytotoxic T cells detect on tumor cells? 1. Self antigens (to which tolerance is incomplete) 2. Neo-antigens, epitopes that are truly foreign Three subclasses: a). Melanocyte differentiation antigens (e.g. Mart-I) b). Cancer-Germline antigens (e.g. NY-ESO-1) c). Overexpressed antigens

20 What do tumor-specific cytotoxic T cells detect on tumor cells? 1. Self antigens (to which tolerance is incomplete) 2. Neo-antigens, epitopes that are truly foreign No viral antigens in melanoma Very large number of UV-induced mutations Could yield epitopes that are recognized by T cells (but to a large extent patient-specific antigens)

21 Numberof non-synomynoussomaticmutations over differenttumortypes Alexandrov et al., Nature 2013

22 TMB isan independantbiomarker, increasingthe likelihood a tumour is recognized as foreign High probabilty of neoantigens Lawrence, Nature 2015; Alexandrov, Nature 2013; Schumacher & Schreiber Science 2016

23 Tools for high-throughput analysis of neo-antigen specific CD8 T cell responses: Toebes et al. Nat Med 2006 Bakker et al. PNAS 2008 Hadrup et al. Nat Methods 2009 Kvistborg et al. Science Transl Med 2014 Allows analysis of T cell responses against 100s-1000s of (predicted) antigens

24 Does TIL therapy induce strong T cell responses against shared self antigens? T cell responses against self antigens are detectable but of a very low magnitude % % % > 4.99 % Young CD8 enriched TIL (NIH) Young TIL (Ella) Selected TIL Patient LR LN KS MV CR ER MA LD SW HE AS RE OJ AS MG NJ BJ(f)* SC* 57SV 63SM 51VS 60SD 41BA 52SD 14PA 09BY 31YR PS OM BJ(m) SM ER CR BM CJ AD OE CT MDA Mart-1 ELA gp100 IMD gp100 YLE gp100 VLY gp100 AML gp100 KTW TRP2 VYD TRP2 SVY NY-MEL 1 VLH CML28 AVL Mage A4 GVY MAGE A10 GLY MageB1, B2 FLW MAGE C2 LLF MAGE C2 ALK NY-ESO 1 SLL HERV K mel MLA SSX-2 KAS GnTV VLP GnT-V VLP10mer Meloe-1 TLN Telomerase RLF Bing 4 CQW Clinical response NR NR NR PR PR NR NR PR PR PR NR NR NR NR PR NR NR CR PR NR PR NR NR PR CR NR NR PR PR CR PR PR NR NR CR NR

25 Developing a strategy for analysis of neo-antigen-specific T cell responses Generate map of tumorspecific mutations (DNASeq: exome, whole genome) Determine which mutated genes are expressed (RNASeq) HLA-A2 HLA-B7 HLA-C2 MDLVLNELVISLIVESKLLE Predict epitopes for each mutation per HLA-allele in silico = antigenome T cell Screen for T cell recognition of mutated epitope

26 Analyzing the neo-antigen-specific T cell repertoire in human cancer? Excise tumor Isolate tumor cells Isolate tumor-infiltrating T cells Identify tumor-specific mutations Screen for T cell reactivity Predict potential T cell epitopes

27 M10TIL003: complete response upon TIL therapy R e d u c tio n in tu m o r Tumor b u rd burden e n Months post infusion of TIL Months post infusion of TIL 48

28 Strong neo-antigen specific T cell responses in the infusion product TIL infusion product VARS T>M MYLK G>V WDR1 N>K LRP3 T>S RBM12 S>L

29 Profound effect of TIL therapy on the neo-antigen specific T cell pool TIL infusion product VARS T>M MYLK G>V WDR1 N>K LRP3 T>S RBM12 S>L Peripheral blood Pre therapy 2 months 6 months 12 months 34 months >450 fold increase in neo-antigen specific T cell reactivity upon TIL therapy

30 Analysis of T cell responses against self antigens in clinically effective TIL products TIL therapy leads to a significant increase in the number of tumor-reactive T cell responses against the group of shared antigens These T cell responses are however of a surprisingly low magnitude In melanoma TIL oftentimes are reactive to neoantigens. The responses appear to be of higher magnitude and can be found within CD8 and CD4 TIL We assume that the anti-tumor immunity is mediated by both classes of antigen-specific T cells, but that it is likely that the neoantigen-specific T cells are of higher importance for the response.

31 Stevanovicet al., J ClinOncol 2015

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35 Alternatives to adoptive T cell therapy: transferring TCRs rather than T cells Possible advantages: No requirement for in vitro expansion of autologous tumor-specific T cells One set of good TCRs could serve many

36 Adoptivecelltherapyplatforms June, Riddell, Schumacher 2015 Science Trans Med

37 Infusionof gene-modifiedt cells Kershaw et al. Nat Rev Cancer 2013

38 Genetically modified peripheral blood lymphocytes Mouse transgenic for human TCR gene locus and MHC cl I Modified from: Restifo et al., Nature Rev Immunol (2012)

39 Schedule of treatment Patient: Informed consent + screening Leukapheresis Start chemotherapy: Cyclophosphamide + fludarabin -7 0 Preparation of gene modified T cells Infusion of transduced T cells (High dose IL-2) mnd 1, 2, 3, 6 Monitoring response and survival

40 Feasibility of TCR gene transfer in the clinic CT scan of liver metastasis in patient treated with TCR-modified T cells Clinical data with TCRs specific for melanocyte differentiation antigens (expression on melanoma and healthy melanocytes) Clinical responses but also (acceptable) on-target toxicity

41 Robbins et al., J ClinOncol 2013 NY-eso-1 TCR gene modified T cells

42 NY-eso-1 TCR gene modified T cells

43 Molecular mimicry between MAGE-A3 peptide and titin peptide MAG-IC3 TCR MAGE-A3 peptide green Titin peptide red HLA-A*0101 Raman et al. Sci Rep 2016

44 Choice of target is critical! Clinical data with TCR specific for carcinoembryonic antigen (expression on colorectal cancer and healthy colonic epithelium) Modest clinical responses with substantial on-target toxicity

45 On-target toxicity of MART-1specific TCR gene therapy Rohaan et al. Unpublished

46 On-target toxicity of MART-1-specific TCR gene therapy: vitiligo Pre 5 months Clinical data with TCRs specific for melanocyte differentiation antigens (expression on melanoma and healthy melanocytes) Clinical responses but also (acceptable) on-target toxicity

47 Adoptivecelltherapyforthetreatment of cancer Adoptive T cell therapy with patient-derived T cells can mediate cancer regression in melanoma patients T cell responses against self antigens are enhanced by these T cell products but are nevertheless weak It is now possible to also evaluate the contribution of T cell responses against patient-specific neo-antigens - We need to find out which T cells matter most Genetic engineering of tumor-specific T cell responses is feasible - Makes adoptive T cell therapy feasible for the (many) tumor types for which TIL can not be grown - Early clinical data demonstrate feasibility and clinical potential - Antigen choice is critical - More advanced engineering strategies are in development - Will allow the design of T cells that carry out desired functions on command