The Immuno‐Oncology Revolution Continues

CATALYST: The Immuno‐oncology Revolution Continues: A 3D View Chapter 3: Resistance or Nonresponse to Treatment Mario Sznol, MD Professor of Medicine (Medical Oncology) Co‐Director, Cancer Immunology Program at Yale Cancer Center New Haven, CT Disclosures

Dr. Sznol has disclosed that he is a consultant for AbbVie, Allakos, Almac, AstraZeneca/Medimmune, Biodesix, Bristol‐ Myers Squibb, Genentech/Roche, Genmab, Hinge, Innate Pharma, Immunocore, Modulate Therapeutics, Molecular Partners, Newlink Genetics, Novartis, Torque, and Seattle Genetics. Dr. Sznol is also on scientific advisory boards for Adaptimmine, Lyciera, Omniox, Pieris, and Symphogen.

This activity is supported by an educational grant from Bristol‐Myers Squibb. CME Objectives

• Discuss the pathophysiology of adult malignancies with a focus on tumor immunosurveillance and immune evasion • Review significant advances and unmet medical needs associated with currently available immuno‐oncology therapies, including innate and adaptive resistance mechanisms (eg, T‐cell exhaustion) • Describe immune pathways that may be targeted to overcome immune‐evasion mechanisms and emerging clinical data on novel immuno‐oncology agents FDA‐Approved Cancer Immune Checkpoint Inhibitors

Agent Target Cancer Indication(s) PD‐1/PD‐L1 Melanoma; NSCLC; metastatic SCLC; intermediate/advanced RCC; Nivolumab PD‐1 HCC; cHL; HNSCC; and urothelial and MSI‐H/dMMR cancers Melanoma; NSCLC; HNSCC; cHL; PMBCL; HCC; and urothelial, Pembrolizumab PD‐1 MSI‐H/dMMR, gastric, cervical, and Merkel cell cancers Atezolizumab PD‐L1 NSCLC; TNBC; urothelial carcinoma Avelumab PD‐L1 Urothelial and Merkel cell cancers Durvalumab PD‐L1 Urothelial carcinoma; stage III NSCLC CTLA‐4 Ipilimumab CTLA‐4 Melanoma; RCC; MSI‐H/dMMR cancer

NSCLC: non‐small cell lung cancer; SCLC: small‐cell lung cancer; HNSCC: head and neck squamous cell cancer; TNBC: triple‐negative breast cancer; cHL: classical Hodgkin lymphoma; PMBCL: primary mediastinal large B‐cell lymphoma; MSI‐H: microsatellite instability‐high cancer; dMMR: mismatch repair deficient; CRC: colorectal cancer; RCC: renal cell carcinoma; CLL: chronic lymphocytic leukemia; NHL: non‐Hodgkin’s lymphoma; B‐CLL; B‐cell chronic lymphocytic leukemia Please see prescribing information for each agent for full indications, notes and stipulations for use. Indications accurate as of March 20, 2019. Predictors for Clinical Response to Anti‐PD‐1/PD‐L1 Pathway Blockade

• PD‐L1 expression – (tumor, tumor‐infiltrating immune cells) • Presence of interferon‐gamma (or T‐effector) gene signature • High tumor mutation burden (DNA sequencing or RNA‐seq, dMMR, MSI‐high)

Possibly reflect a pre‐existent T‐cell response to tumor • Number of CD8+ T cells at tumor invasive margin • Presence of tumor stromal CD8+ T cells • Clonality of intratumoral T‐cells • Intratumoral CD8+ T cell quality/type and quantity

Taube JM, et al. Clin Cancer Res. 2014;20:5064‐5074; Zou W, et al. Sci Transl Med. 2016; 8(328): 328rv4. doi:10.1126/scitranslmed.aad7118 . Primary and Acquired Resistance

Primary PD Resistance Tumor Regression Acquired PD or prolonged Resistance stable disease

Sensitive or Tumor PD Acquired Regression Stop therapy Resistance

Sharma P, et al. Cell. 2017;168:707‐723. Summary of Immune Checkpoint Inhibitor Non‐Response or Resistance • Genetic component? • Low tumor mutation burden • Lower microbiome diversity/presence or Priming – Minimal to no absence of bacterial species T‐cell response • Increased/stabilized beta catenin • Failure of Sting activation • PTEN loss (dependent on VEGF) Exclusion/Traffic signals? • Increased VEGF Or lack of/inadequate activation • Tumor Hypoxia of tumor APC • IPRES signature/angiogenesis/ETM transition • Increase in Myeloid cell signature Feedback negative • Increased peripheral complement activation, regulation +/‐ lack of wound healing, acute phase reactants additional agonist signals • Tumor/TME metabolism (glucose) • Induction of T‐cell regulatory mechanisms (IDO, Tim‐3, other immune checkpoints) or T‐cell exhaustion • Increase in tumor DNA copy number loss (immune related genes) Tumor cell or • JAK mutations (IFN‐ƴ pathway signaling) T‐cell insensitivity • Beta‐2 microglobulin/HLA loss Tumor Intrinsic Mechanisms to Avoid Immune Recognition

Sharma P, et al. Cell. 2017;168:707‐723. Please put on your 3D glasses Resistance or Nonresponse to Treatment 3D Video

(Note: this slide should not be shown; it is the placeholder for the video) Multiple Pathways Modulate T Cell and APC Activity

APC = Antigen presenting cells. Midan A, Curran MA. Cancer Immunol,Immunother. 2015;64:885‐892. Actions of Approved and Investigational Agents

Anti‐CD40, FLT3, TLR agonists

Create new tumor‐specific STING agonists, T‐VEC, Other oncolytic viruses, T‐cells or enhance Vaccines, Chemotherapy, Targeted agents, Epigenetic in vivo Ag Modifiers, MEKi presentation

Adoptive Transfer: CAR‐T

Wang M et al. Biochimica et Biophysica Acta. Reviews on Cancer. 2018; https://www.sciencedirect.com/science/article/pii/S0304419X18302026 Actions of Approved and Investigational Agents (cont)

CTLA‐4, others

Enhancing TCR signaling

Expansion and Transcription factor agonists Increase Function of Ag‐specific Cytokines and Modified Cytokines T cells

Co‐stimulatory Agonists – 4‐1BB, OX‐40, GITR, ICOS, CD27

Adoptive Transfer: TIL, CAR‐T

Co‐opt non‐ Activate with TCR‐CD3 Constructs (CEA, gp100) specific TIL

Wang M et al. Biochimica et Biophysica Acta. Reviews on Cancer. 2018; https://www.sciencedirect.com/science/article/pii/S0304419X18302026 Co‐stimulatory and Inhibitory Immune Checkpoint Molecules, T‐Cell Responses, and Interactions

Checkpoints CTLA‐4, LAG3, TIM3, TIGIT, B7‐H3, B7‐H4, PD‐1H (Vista), within tumor CD200, CEACAM1, KIR

HDACi, MER‐TKi, CCR2i, CSF‐1Ri, CD40, CKITi, ibrutinib, MDSC/TAMS Anti‐CD47 (‘Don’t Eat Me Signals’ ), SIGLECs

Treg Anti‐CCR4, anti‐CTLA‐4, anti‐CD25

Inhibitory Antibodies and small molecule inhibitors of TGF‐beta or Cytokines its receptors

Hypoxia/ Adenosine 2AR inhibitors Adenosine Anti‐CD39, anti‐CD73

Metabolic IDO inhibitors, Cox2 inhibitors, modulators of tumor/ Inhibitors and T‐cell glucose consumption (PPAR‐alpha inhibitors) Prostaglandins

Barriers to Anti‐VEGF, anti‐SEMA‐4D, anti‐CTLA‐4 T‐cell infiltration

Wang M et al. Biochimica et Biophysica Acta. Reviews on Cancer. 2018; https://www.sciencedirect.com/science/article/pii/S0304419X18302026 Potential Practical Use of Biomarkers

* Odds for benefit and quality of benefit Biomarker 3 for Biomarker 1* for Optimal anti‐ maximal effect – PD‐1/PD‐L1 tumor response stop therapy, no pathway further therapy

Sub‐optimal anti‐ Add therapy X to Biomarker 2 tumor response PD‐1/PD‐L1 blockade

Add therapy X/Y/Z to PD‐1/PD‐L1 blockade No anti‐tumor response Immune therapy X/Y/Z without Biomarker x1, PD‐1/PD‐L1 blockade x2, x3 for alternative therapies Alternative non‐immune therapy Biomarker 1 and Biomarker 2 could be assessed early post‐treatment Conclusions

• FDA‐approved immunotherapy inhibits either (1) CTLA‐4, or (2) the PD‐1/PD‐L1 pathways. These options release natural brakes on the immune system, increasing activation of immunity with beneficial effects on T cells.

• Several predictors of response to anti PD‐1/PD‐L1 blockade exist, including PD‐L1 expression, presence of IFN‐γ, and high tumor mutation burden

• Mechanisms of resistance/non‐response may occur through several pathways, including priming, exclusion/traffic signals, regulation of agonist signals, tumor cell/t‐cell insensitivity, and others UP NEXT: CHAPTER 4

CATALYST: The Immuno‐oncology Revolution Continues: A 3D View Chapter 4: Investigational Treatment

Jeffrey Weber, MD PhD Deputy Director, Perlmutter Cancer Center Co‐Director, Melanoma Research Program New York University Langone Medical Center New York, NY