Combining radiation therapy with immunotherapy: clinical translation. Silvia C Formenti, M.D.

Transcription

1 Combining radiation therapy with immunotherapy: clinical translation Silvia C Formenti, M.D.

2 Disclosures Consultant/Speaker: Bristol Myers Squibb, Varian, Jensen, Elekta, Regeneron Principal Investigator: NIH 1 S10 RR Preclinical Research Irradiator NCI R01CA Immunomodulation of breast cancer via TLR7 agonist IMQ and RT DOD BC / W81XWH Multi-Team Award (MTA) Radiation-Induced Vaccination to Breast Cancer 13-A Breast Cancer Research Foundation Targeting key inhibitory pathways to improve radiation-induced vaccination in breast cancer

3 How do standard anti-cancer treatments interfere with this landscape? Dunn et al, Nature Immunology 2002 Koebel et al, Nature 2007

4 IN SITU VACCINATION HYPOTHESIS RT TUMOR CD4 T cell IL-12 CD8 T cell IJROBP, 2005 IJROBP, 2012

5 Immunogenic cell death induced by treatment is defined by 3 molecular signals TUMOR CRT HMGB-1!!!! TLR4 DC C IL-1β ATP P2RX7 CD4 T cell CD8 T cell CTL activation IL-12 IL-2 γifn CRT, the eat me signal calreticulin translocates to cell surface (Obeid et al., Nat Med 2007, 13:54-61; Cell Death Differ 2007, 14:1848) HMGB-1, a damage associated molecular pattern (DAMP) binds to TLR4 to promote cross-presentation of tumor-derived antigens (Apetoh et al., Nat Med 2007, 13:1050) ATP released by dying cells binds to P2RX7 purigergic receptor leading to inflammasome activation and IL-1β production (Ghiringhelli et al., Nat Med 2009, 15:1170)

6 CRT In vitro assay for RT-induced ICD HMGB1 ATP Encouse Golden Oncoimmunology, 2014

7 Pro-immunogenic effects of ionizing radiation 1. Apetoh, Nature Med 2007 Golden, Oncoimmunology Chakravarty, Can Res 1998 Nikitina, Int J Can 2001 Liao, JI 2004 Gulley, Clin Can Res, Lugade, JI 2005 Demaria, Clin Can Res 2005 Reits, JEM 2006 Brody, JCO 2010 Burnette, Can Research Matsumura JI, 2008 Klug, Cancer Cell Lugade, JI Chakraborty, JI 2003 Chakraborty, Can Res 2004 Newcomb, Clin Can Res Demaria, IJROBP 2004 Ruocco, JCI 2012 Chen and Mellman, Immunity, 2013

8 Abscopal Effect Effect of ionizing radiation on cancer outside the radiation field Latin ab (position away from) and scopus (mark or target) Abscopal response *Mole RJ. Whole body irradiation - radiology or medicine? Br J Radiol 1953; 26:234 Why are abscopal effects so rare? IJROBP 2004; Lancet Oncology 2009

9 IMMUNOSUPPRESSION DOMINATES IN ESTABLISHED TUMORS A need to combine radiotherapy with immunotherapy Vesely MD, 2011, Annu.Rev.Immunol 29:235-71

10 NYU experience in combining immunotherapy strategies with radiation Priming phase : FLT-3L/GM-CSF TLR agonists Effector phase: Anti-CTLA4 Anti-PD-1 Anti-TGFβ

11 Hypothesis: Ionizing radiation can stimulate anti-tumor immunity by generating an in situ vaccine - and combination with immunotherapy may uncover this effect Day: 0 67NR 5x10 4 or 10 5 each sides, primary R and secondary L 20 RT 2 Gy Flt3-L (0.5mg/kg) R primary L secondary RT X BALB/C mice injected at two separate sites with the \ syngeneic mammary carcinoma 67NR cell line

12 RT+Flt3-L : systemic anti-cancer effects Irradiated non-irradiated Int J Radiation Oncology Biol Phys 2004

13 Abscopal Effect is abrogated in nude mice Int J Radiation Oncology Biol Phys 2004

14 NYU 0258 Abscopal trial RT+GM-CSF in metastatic solid tumors DAY Week 1, 2 RT Week 4, 5 RT Week 2, 3 Week 5, 6 GM-CSF GM-CSF Within 2 weeks from study entry: Baseline measurements CT and PET End of Week 3 Assess clinical response Week 7-8 Assess clinical response and CT/PET response RT 3.5GyX10 GM-CSF 125 µg/m 2

15 Abscopal effect 10/37 (27%) Abscopal effect and survival, 37 patients (NYU 02-58) A. Abscopal responders likely to be patients already more immunocompetent ASTRO 2012

16 Imiquimod Study (IMQ) Design: is a synthetic Timeline TLR-7 agonist IMQ topical cream FDA approved for treatment of superficial basal cell carcinoma, actinic keratosis, and external genital warts Clin Can Res, 2012

17 TLR agonists and RT+/-Cytoxan

18 TLR7 agonist Imiquimod: Abscopal response Baseline vs post-tx photo of RT + Imiquimod) Baseline vs post-tx photo of control area (NO) Imiquimod Response at a distant site of disease 10/ / /2013 NCI-R01 Immunomodulation of breast cancer via TLR7 agonist IMQ and RT,

19 NYU experience in combining immunotherapy strategies with radiation Priming phase : FLT-3L/GM-CSF TLR agonists Effector phase: Anti-CTLA4 Anti-PD-1 Anti-TGFβ

20 Blockade of CTLA-4 is required for anti-tumor T cell priming by radiation in vivo Demaria et al., Clin Cancer Res 2005

21 Patient with Metastatic NSCLC Progressing after 3 lines of chemo and chest RT: Multiple lung, bone and liver metastasis RT to one liver met6 Gy X 5 ( TD 30 GY) Ipilimumab, 3 mg/kg, after first RT q3 weeks, X 4 cycles Golden et al Cancer Immunology Research, 2014

22 Metastatic NSCLC: Response to RT+ipilimumab

23 H&E CD8 TIA-1 Ratio CD8/FoxP3 cells/hpf cells/hpf CD8 Fox-P Cancer Imm. Research, 2014

24 Clinical and radiological CR at one year: currently NED at 25 m

25 12 ongoing trials testing testing combinations of RT and Ipilimumab: At NYU: NCT

26 799 patients randomized Site: bone mets Dose : 8 Gy, single fraction Time: RT within 2 days from IPI, then anytime during IPI

27 Study failed to meet its main endpoint Study powered to detect a 4 month difference in median overall survival (15.8 versus 12 months) Curves split after 6 months Lancet Oncology 2014

28 Difference in progression free survival At 6 months 30.7% versus 18.1% Is PFS good enough of an endpoint?

29 MANY QUESTIONS REMAIN: - Optimal site to irradiate in metastatic disease - Patient selection - Sequencing of radiotherapy/immunotherapy - RT dose and fractionation - Best combinations

30 Inhibition of tumor lung metastases is seen only when radiation to the primary tumor is given with anti-tgfβ mab 4T1: spontaneous systemic micro-metastases Lungs micrometastases RT primary tumor Tumor volume (mm 3 ) ** * ** Lungs metastases *** *** *** Days post inoculation (submitted for publication)

31 Fresolimumab+RT TRIAL, in metastatic breast cancer MTA from DOD

32 Fresolimumab and radiation (7.5 GyX3) to one lesion Patient #2 11/10/11 before tx 12/19/11 a month after first TX 2/27/12 Last PET/CT 11/18/11 First Fresolimumab+RT to liver 2/8/12 Second Freso+RT to breast skin Response reported as irsd, 28% reduction, no new lesions,

33 Accrued 22 patients:11 per arm Comparison of OS and PFS based on fresolimumab dose ( arm A=10mg, arm B=1 mg)

34 PD-1 blockade improves therapeutic efficacy of RT+TGFbeta neutralization Vanpouille-Box et al., In preparation

35 Clinical translation RT combination with: Trial/ tumor site accrual Flt3L (Demaria et al., Int J Radiat Oncol Biol Phys, 2004) Proof of principle abscopal trial (met disease all sites) NYU /37 anti-ctla-4 (Demaria et al., Clin Cancer Res 2005; Matsumura et al., J Immunol 2008; Pilones et al., Clin Cancer Res 2009; Dewan et al., Clin Cancer Res 2009; Ruocco et al., J Clin Invest 2012) Ipilimumab RT randomized Met melanoma S Ipilimumab -RT Met NSCLC trial S /48 18/29 TLR7-agonist (Dewan et al. Clin Cancer Res 2012) Imiquimod-RT trial NCT /29 anti-tgfβ (Bouquet et al Clin Cancer Res 2012)2 Fresolimumab-RT Randomized NCT /24

36 NYU Radiation and Immunity Research Incubator RT/IT combinations IN VITRO ICD Assay (NIH) S10 RR Preclinical Research Irradiator Funding: $469,716 IN VIVO models Clinical protocol

37 Summary Preclinical and clinical evidence suggests that local radiotherapy can contribute to the efficacy of cancer immunotherapy, by rendering the irradiated tumor more immunogenic Radiotherapy can be harnessed as an adjuvant to immunotherapy as it may convert non-responding patients to responders to the same immunotherapy Dose/fractionation and sequencing of radiotherapy need to be explored in combination with each immunotherapy strategies, in prospective PHASE I-II clinical trials

38 NYU RT and Immunity Team MH Barcellos-Hoff Ph.D. Encouse Golden M.D.,Ph.D. Mike Dustin Ph.D. Sandra Demaria M.D. Claire Vanpouille-Box Ph.D. Karsten Pilones Ph D. Keith DeWyngaert, Ph.D. Maria Fenton-Kerimian, N.P. Our patients