State of the Art in Development of Immunotherapy. Alex A. Adjei. ESMO AFRICA Cape Town February 15, MFMER slide-1

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1 State of the Art in Development of Immunotherapy Alex A. Adjei ESMO AFRICA Cape Town February 15, MFMER slide-1

2 DISCLOSURE OF INTEREST Alex A. Adjei Institutional financial interests : Clinical trial Funding : MSD, Piqur, Macrogenics, Kura 2016 MFMER slide-2

3 Two Types of Immune Responses Provide Extended Protection Adaptive Immunity CANCEROUS CELLS Innate Immunity Physical Barriers 1. Murphy K. Janeway s Immunobiology. 8th ed. New York, NY: Garland Science; Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; MFMER slide-3

4 Innate Immune Cells Granulocytes Engulf microorganisms or kill them by releasing toxic molecules Macrophages Reside in almost all tissues, destroy microorganisms and dead cells and help recruitment of other immune cells Monocyttees Ingest foreign particles, are the precursors of macrophages APCs Macrophage B cell Dendritic cell Found in lymphoid and non-lymphoid tissue, activate naïve T cells, help trigger adaptive immune response Tumor cell Cytotoxic T cell CD8 + cells, also called cytotoxic T lymphocytes (CTL), kill virus-infected cells and tumor cells Immune Effector Cells Helper T cell CD4 + cells produce cytokines that help activate various cells and support B-cell antibody production Tregs Regulatory T cells (Tregs) suppress the activity of many cell types and help control immune responses 2016 MFMER slide-4

5 Proper T-Cell Activation Requires 2 Signals To be properly activated, a T cell MUST receive 2 signals Binding of an MHC-antigen complex to TCR Binding of a second costimulatory signal This initiates intracellular signaling that activates the T cell, which can then kill infected or cancer cells or help support other immune functions T cell Costimulation Effector functions Antigen MHC APC: Tumor cell APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor. Image 2012 from Janeway s Immunobiology, Eighth Edition by Murphy. Adapted by permission of Garland Science/Taylor & Francis LLC. 1. Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; Mellman I et al. Nature. 2011;480(7378): MFMER slide-5

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7 Targeting Immune Mechanisms in the Tumor Microenvironment Stromal cell Effector cell Cytokines 1 Stimulates a nonspecific immune response by boosting the activity of immune effector cells and stromal cells at the tumor site Tumorinfiltrating T cells Adoptive T-cell Transfer 2 Increases the frequency of tumor-antigen-specific T cells by growing T cells harvested from a tumor sample in vitro and then reinfusing them Therapeutic Vaccines 2 Designed to generate a specific active immune response against tumor antigens Immune Checkpoint Inhibition and Costimulatory Molecule Agonism 3,4 Therapeutic targeting of immune checkpoints is designed to reverse tumoral suppression of T-cell activity, while agonism of costimulatory molecules aims to enhance tumor-specific T-cell activation TIL = tumor-infiltrating lymphocytes 1. Lee S, Margolin K. Cancers (Basel). 2011;3(4): Mellman I et al. Nature. 2011;480(7378): Spranger S et al. J Immunother Cancer. 2013;1: Schaer DA et al. J Immunother Cancer. 2014;2: MFMER slide-7

8 Cosignaling Molecules Contribute to Immune Regulation Cosignaling regulates T-cell activation Signaling via costimulatory molecules (eg, CD28, GITR) promotes T-cell activation Signaling via coinhibitory molecules (eg, PD-1, LAG-3), also termed immune checkpoints, suppresses T-cell activation APCs can express the signaling partners of these costimulatory and coinhibitory molecules and direct T-cell accordingly Costimulatory molecules Coinhibitory molecules 1. Pardoll DM. Nat Rev Cancer. 2012;12(4): Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; Mellman I et al. Nature. 2011;480(7378): MFMER slide-8

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10 Lesson 1 The Checkpoint Inhibitors really work!!! 2016 MFMER slide-10

11 64-year-old male with squamous NSCLC s/p R lobectomy, progressed on cisplatin + gemcitabine, docetaxel, erlotinib. Treated with Atezolizumab (1200mg iv q 3wks) Baseline Post C2 (Week 6) Post C4 (Week 12) 2016 MFMER slide-11

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13 Immune checkpoint inhibitors have demonstrated responses across several tumour types Change from baseline in sum of longest diameter of target lesion, % Breast cancer treated with pembrolizumab 1 NSCLC treated with durvalumab * ORR 19% PD 44% Confirmed complete response (nodal disease) Confirmed partial response Stable disease Progressive disease Best change from baseline (%) PD-L1+ ORR 27% PD NA PD-L1- ORR 5% PD NA Maximum SLD reduction from baseline (%) * UC IC2/3 treated with atezolizumab 3 ORR 27% PD 43% Complete response Partial response Progressive disease Stable disease 2016 MFMER slide-13

14 Spectrum of Activity of Immune Checkpoint Inhibitors Long lasting responses in patients with: Melanoma (30-35%) NSCLC (20-25%) Bladder (25%) Hodgkin s (65-85%) Merkel cell carcinoma (71%) Head and neck Gastric Ovarian Colorectal Liver Mesothelioma SCLC MSI high/mmr tumors GBM Eso phageal HCC Mes othe - liom atnb C Ovar ian Mel PD- 1/PD-L1 Blockad e MSIhigh CRC RCC NSC LC Blad der HNS CC Hod B- gkin cell NHL

15 U.S. FDA Approved PD1/PDL1 Axis Inhibitors Melanoma Non-Small Cell Lung Ca Renal Cell Ca Urothelial Ca Hodgkins Lymphoma Head & Neck Ca Merkel Cell Ca MSI-high/ dmmr Ca Gastric CA Hepatocellular CA Pembrolizumab, Nivolumab, Nivolumab + Ipilimumab Nivolumab, Pembrolizumab, Atezolizumab, Pembrolizumab + Carboplatin/ Pemetrexed Nivolumab, Pembrolizumab Atezolizumab, Pembrolizumab, Avelumab, Durvalumab, Nivolumab Nivolumab, Pembrolizumab Pembrolizumab, Nivolumab Avelumab Pembrolizumab, Nivolumab (if Colon Ca) Pembrolizumab Nivolumab 2016 MFMER slide-15

16 Lesson 2 There are durable responses Could some patients with metastatic disease be cured? 2016 MFMER slide-16

17 Female (66 y.o) with squamous cell lung cancer s/p 3 chemotherapy regimenss. Referred to our phase I clinic. Received nivolumab in 2011 January 2011 December MFMER slide-17

18 Long term survival in patients with heavily pretreated metastatic NSCLC CA Year Update: Phase 1 Nivolumab in Advanced NSCLC 100 OS (%) y OS, 42% 2 y OS, 24% 3 y OS, 18% 5 y OS, 16% Median OS (95% CI), mo Overall (N = 129) 9.9 (7.8, 12.4) No. at Risk Years Brahmer J, AACR 2017 a There were 3 deaths between 3 and 5 years, all due to disease progression; 1 surviving patient was censored for OS prior to 5 years (OS: months) 2016 MFMER slide-18

19 Lesson 3 How long should we treat? MFMER slide-19

20 A Signal CheckMate 153 Exploratory Analysis Improvement in PFS (HR 0.42), 1 year PFS: 65% vs 40% Improvement in PFS independent from RR Trend in OS (HR 0.63) Some stabilizations by reexposure Spigel D et al, ESMO 2017; abstract 1297O 2016 MFMER slide-20

21 Lessons learned 4 Response to treatment can be atypical : Pseudoprogression 2016 MFMER slide-21

22 Pseudoprogression with pembrolizumab response after initial progression Case courtesy of Caroline Robert, Gustave Roussy, Villejuif 2016 MFMER slide-22

23 Ipilimumab Responses After the Appearance and Subsequent Disappearance of New Lesions Pre-Treatment July 2006 Wk 12: Progression 3 mg/kg Ipilimumab q3wks X 4 New lesions Wk 20: Regression Wk 36: Still Regressing Wolchok et al, 2008a MFMER slide-23

24 Pseudo-progression may reflect development of antitumor immunity Antitumor immune response can appear as disease progression (tumor growth or appearance of new lesions) known as pseudo-progression 1 Pseudo-progression may be misclassified as disease progression BASELINE ASSESSMENT FIRST ASSESSMENT LATER ASSESSMENT Disease progression Pseudo-progression T cell NK cell Although uncommon, pseudo-progression should be considered until disease progression can be confirmed 2016 MFMER slide-24

25 General Fatigue, asthenia, fever, chills, infusion related reaction Lesson #5 : Unusual Toxicities Occur: Immune related Adverse Events (IRAEs) Inflammatory processes affecting any organ system Distinct mechanism of action from traditional chemotherapy-related side effects Evaluation and management are unique to this class of drugs MSK Arthralgia, myalgia, arthritis, myosititis May be exacerbated by underlying autoimmune conditions/presence of autoantibodies

26 Case 72 y/o with metastatic squamous cell lung cancer Docetaxel/carboplatin x 4 cycles Gemcitabine/carboplatin x 4 cycles Nivolumab x 8 cycles with PR but new infiltrates Bronchoscopy with BAL and biopsy 2016 MFMER slide-26

27 AFB, PCR +ve for M. tuberculosis Diffuse lymphocytic infiltration were in the alveolae Fujita et al, JTO MFMER slide-27

28 Can we Identify patients who will benefit from immunotherapy? MFMER slide-28

29 What is the Ideal Biomarker? Validated Quantifiable or binary Sensitive and specific. Simple and adaptable to clinical use, with a quick turnaround time Present in easily accessible tissues 2016 MFMER slide-29

30 We know that PD-L1 expression has clinical relevance PD-L1+ cancers demonstrate higher response rates in a wide variety of cancers regardless of the PD-L1 assay or the PD-1/PD-L1 agent used Adapted from Callahan: ASCO MFMER slide-30

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32 Tumor Mutational Burden (TMB) 2016 MFMER slide-32

33 High TMB is associated with response to checkpoint inhibition DCB: Durable clinical benefit (PR/SD >6months) NDB: No durable benefit Rizvi. Science MFMER slide-33

34 What mutations to count in TMB Synonymous SNVs Nonsynonymous Rizvi. WCLC MFMER slide-34

35 Tumor Mutational Burden CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC Tumor DNA Tumor exome data Whole exome sequencing a Somatic missense mutations TMB Germline DNA (blood) Germline exome data TMB tertile Total missense mutations, no. Low 0 to <100 Medium 100 to 242 High TMB - Definition 243 a DNA was sequenced on the Illumina HiSeq 2500 using bp paired-end reads; an average of 84 and 89 million reads were sequenced per tumor and germline sample, respectively (average 84.6 and 93 the mean target coverage, respectively) Peters, S et al. AACR MFMER slide-35

36 S. Peters et al, AACR MFMER slide-36

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38 Cellular infiltrates within the Tumour microenvironment Kerkar & Restifo. Cancer Res MFMER slide-38

39 Inhibiting PD-1-mediated adaptive immune resistance Anti-PD-1 Anti-PD-L1 Melanoma cell or tumor macrophage Interferons Taube et al. Sci Transl Med 2012 Tumeh et al. Nature MFMER slide-39

40 Inhibiting PD-1-mediated adaptive immune resistance Anti-PD-1 Anti-PD-L1 Melanoma cell or tumor macrophage Interferons Tumeh et al. Nature MFMER slide-40

41 Evolution of CD8+ T-cells, According to Treatment Outcome IHC Analysis of CD8+ T-cells in samples obtained before and during anti-pd1 treatment Paul C. Tumeh, Christina L. Harview, I. Peter Shintaku, Emma J. M. Taylor 2016 MFMER slide-41

42 Management of cancer in the post-anti-pd-1/l1 era Anti-PD-1/anti-PD-L1 Bring T cells into tumors: + anti-ctla4 + immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + IDO or macrophage inhibitors + targeted therapies Generate T cells: Vaccines TCR engineered ACT CAR engineered ACT 2016 MFMER slide-42

43 Planned and ongoing trials 2016 MFMER slide-43

44 Pertinent issues with Immunotherapy in Africa MFMER slide-44

45 The Microbiome and Immunotherapy ll 1 Lita Proctor HMP 2016 MFMER slide-45

46 >10 14 microorganisms in GIT making us 90% bugs and 10% us!

47 Composition and luminal concentrations of dominant microbial species in various regions of the gastrointestinal tract. Gastroenterology (2) 2016 MFMER slide-47

48 The gut microbiota during the human lifespan 2016 MFMER slide-48

49 Fig. 1 Higher gut microbiome diversity is associated with improved response to anti PD-1 immunotherapy in patients with metastatic melanoma. V. Gopalakrishnan et al. Science 2018;359: Published by AAAS 2016 MFMER slide-49

50 The Western Microbiota Diverges from That of Non-Western Populations 2016 MFMER slide-50

51 Checkpoint inhibitors are Expensive Nivolumab $13,800/4 wks Pembrolizumab $12,500/3 wks Atezolizumab $12,500/3 wks Nivolumab/Ipilumumab $256,000/1 year 2016 MFMER slide-51

52 What will be the effect of Endemic Infections? More immunogenic tumors leading to increased responses? Increased incidence of IRAEs? Increased activation of microbial and protozoal infections? MFMER slide-52

53 Summary Immune Checkpoint Inhibitors Have broad durable activity in a large number of tumors Predictors of efficacy are complex and not well understood It is accepted that tumors have to be immunogenic or inflamed with T cell infiltration as a pre-requisite for efficacy Determinants of inflamed tumors may include tumor genomic profile and the host microbiome Combinations with different modalities will be needed to broaden activity These combinations are toxic and expensive Clinical trials need to be performed in less developed countries to understand toxicity and efficacy patterns 2016 MFMER slide-53

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