catalyst: the immuno‐oncology revolution …...catalyst: the immuno‐oncology revolution...

CATALYST: The Immuno‐oncology Revolution Continues:

A 3D ViewChapter 3: Resistance or Nonresponse to Treatment

Mario Sznol, MDProfessor of Medicine (Medical Oncology)

Co‐Director, Cancer Immunology Program at Yale Cancer CenterNew 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

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 leukemiaPlease see prescribing information for each agent for full indications, notes and stipulations for use. Indications accurate as of March 20, 2019.

Agent Target Cancer Indication(s)PD‐1/PD‐L1

Nivolumab PD‐1Melanoma; NSCLC; metastatic SCLC; intermediate/advanced RCC; HCC; cHL; HNSCC; and urothelial and MSI‐H/dMMR cancers

Pembrolizumab PD‐1Melanoma; NSCLC; HNSCC; cHL; PMBCL; HCC; and urothelial, 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

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

PDPrimaryResistance

TumorRegression or prolonged

stable disease

PD AcquiredResistance

Tumor Regression

PDSensitive or Acquired Resistance Stop therapy

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

absence of bacterial species• Increased/stabilized beta catenin• Failure of Sting activation • PTEN loss (dependent on VEGF) • Increased VEGF• Tumor Hypoxia• IPRES signature/angiogenesis/ETM transition • Increase in Myeloid cell signature • Increased peripheral complement activation,

wound healing, acute phase reactants• 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)• JAK mutations (IFN‐ƴ pathway signaling)• Beta‐2 microglobulin/HLA loss

Priming – Minimal to no T‐cell response

Exclusion/Traffic signals? Or lack of/inadequate activation of tumor APC

Tumor cell or T‐cell insensitivity

Feedback negative regulation +/‐ lack of additional agonist signals

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 Treatment3D Video

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Multiple Pathways Modulate T Cell and APC Activity

APC = Antigen presenting cells.Midan A, Curran MA. Cancer Immunol,Immunother. 2015;64:885‐892.

Anti‐CD40, FLT3, TLR agonists

STING agonists, T‐VEC, Other oncolytic viruses, Vaccines, Chemotherapy, Targeted agents, Epigenetic Modifiers, MEKi

Adoptive Transfer: CAR‐T

Actions of Approved and Investigational Agents

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

Create new tumor‐specific T‐cells or enhance in vivo Ag presentation

Actions of Approved and Investigational Agents (cont)


Expansion and Increase Function of Ag‐specific T cells

Co‐opt non‐specific TIL

CTLA‐4, others

Enhancing TCR signaling

Transcription factor agonists

Cytokines and Modified Cytokines

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

Adoptive Transfer: TIL, CAR‐T

Activate with TCR‐CD3 Constructs (CEA, gp100)

Co‐stimulatory and Inhibitory Immune Checkpoint Molecules, T‐Cell Responses, and Interactions


Checkpoints within tumor

MDSC/TAMS

Treg

Inhibitory Cytokines

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

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

Anti‐CCR4, anti‐CTLA‐4, anti‐CD25

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

Co‐stimulatory and Inhibitory Immune Checkpoint Molecules, T‐Cell Responses, and Interactions (con’t)


Hypoxia/Adenosine

Metabolic Inhibitors and Prostaglandins

Barriers to T‐cell infiltration

Adenosine 2AR inhibitors Anti‐CD39, anti‐CD73

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

Anti‐VEGF, anti‐SEMA‐4D, anti‐CTLA‐4

Co‐stimulatory and Inhibitory Immune Checkpoint Molecules, T‐Cell Responses, and Interactions


Potential Practical Use of Biomarkers

Biomarker 1* for PD‐1/PD‐L1 pathway

Biomarker x1, x2, x3 for alternative therapies

Optimal anti‐tumor response

Sub‐optimal anti‐tumor response

No anti‐tumor response

Biomarker 2

Biomarker 3 for maximal effect –stop therapy, no further therapy

Add therapy X to PD‐1/PD‐L1 blockade

Add therapy X/Y/Z to PD‐1/PD‐L1 blockade

Immune therapy X/Y/Z without PD‐1/PD‐L1 blockade

Alternative non‐immune therapy

* Odds for benefit and quality of benefit

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 ViewChapter 4: Investigational Treatment

Jeffrey Weber, MD PhDDeputy Director, Perlmutter Cancer Center Co‐Director, Melanoma Research Program

New York University Langone Medical Center New York, NY

catalyst: the immuno‐oncology revolution …...catalyst: the immuno‐oncology revolution...

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