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10/10/20171

Immunotherapy UpdatePerspectives from a melanoma oncologist

Katy K. Tsai, MDAssistant Clinical Professor in Cutaneous OncologyHelen Diller Family Comprehensive Cancer Center

6th Asian Health SymposiumLaurel Heights Conference CenterFriday, October 6, 2017

Disclosures

I have nothing to disclose.

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Immunotherapy Landscape

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10/10/20172

Outline

Immunology 101

Cancer Immunotherapy

‒ Definition

‒ Non-specific vs Specific

‒ Mechanisms of Action

Clinical Importance

‒ Applications in Asian Health

Future Directions

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Outline

Immunology 101

Cancer Immunotherapy

‒ Definition

‒ Non-specific vs Specific

‒ Mechanisms of Action

Clinical Importance

‒ Applications in Asian Health

Future Directions

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Immunology 101

Self vs Non-self

Mechanisms of central vs peripheral tolerance

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“I am convinced that the development of aberrant cells occurs very frequently… but that these foci luckily remain completely latent in most humans because of protective mechanisms in the host. If these mechanisms were not existent, cancer would probably develop with incredible frequency.”

Paul Ehrlich (1854-1915)

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10/10/20173

The “Cancer-Immunity Cycle”

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Chen and M

ellm

an, Immunity 2013.

Cancer cells have developed ways to evade the host immune system by taking advantage of mechanisms of peripheral tolerance.

Outline

Immunology 101

Cancer Immunotherapy

‒ Definition

‒ Non-specific vs Specific

‒ Mechanisms of Action

Clinical Importance

‒ Applications in Asian Health

Future Directions

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Cancer Immunotherapy

Clarifying “Immunotherapy” vs “Chemotherapy”

Immunotherapy = treatment that uses the immune system to fight cancer by:

• Providing immune system components to “boost” immune function (non-specific)

• Stimulating/training immune system to work harder and/or smarter to attack cancer cells (specific)

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Types of Immunotherapy (FDA approved)

Non-specific Specific

Cytokines• Interferon• IL-2

Immune checkpoint inhibitors• CTLA-4• PD-1/PD-L1

Oncolytic viruses• T-VEC

Manipulation of T cells• CAR T cells

Vaccines• Sipuleucel-T

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10/10/20174

Immune Checkpoint Inhibition

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ipilimumab (Yervoy)

pembrolizumab(Keytruda) nivolumab (Opdivo)

avelumab (Bavencio)atezolizumab (Tecentriq)durvalumab (Imfinzi)

Buchbinder et al, American Journal of Clinical Oncology, 2016.

CTLA-4 vs PD-1

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• Stops potentially autoreactive T cells at initial stage of naïve T cell activation (lymph node)

• Regulates previously activated T cells at later stages of immune response (peripheral tissues)• CTLA-4 blockade activation +

proliferation of more T cell clones, reduces Treg-mediated immunosuppression

• PD-1 blockade restores activity of antitumor T cells that have become quiescent

CD8 T cell infiltration with pembrolizumab

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Tumeh et al, Nature 2015.

Melanoma response to ipilimumab + nivolumab

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Dec 2016 Sept 2017

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10/10/20175

OS Estimates from CheckMate-037

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RFS Estimates for Adjuvant Immunotherapy

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Oncolytic Viruses

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Tamilargene laherparepvec or T-VEC (Imlygic)

First-in-class intratumoraloncolytic viral therapy

Modified HSV-1 virus

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10/10/20176

T Cell Manipulation

Manipulating patient-specific T cells ex vivo to make them more reactive to specific antigens

Chimeric antigen receptor (CAR) T cells

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CAR T Cell Therapy

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Tisagenlecleucel (Kymriah) approved Aug 2017 for patients up to 25 yo with B cell precursor ALL that is refractory or in second or later relapse

First in class gene therapy; one-time treatment

4-1BB costimulatory domain to enhance cellular expansion, persistence

Vaccines

Long history of attempts to harness adaptive immune system’s ability to recognize cancer antigen to effect antitumor response

Choice of antigen

• Simple peptides (easy to administer but narrow spectrum)

• Whole cell preparations (broader range but costly, time-consuming)

Single-peptide vaccine results have been largely disappointing in melanoma

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Sipuleucel-T (Provenge)

Sole currently approved vaccine-based therapy

OS benefit in castrate-resistant prostate adenocarcinoma

Autologous dendritic-cell preparation targeting prostatic acid phosphatase (PAP)

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10/10/20177

Outline

Immunology 101

Cancer Immunotherapy

‒ Definition

‒ Non-specific vs Specific

‒ Mechanisms of Action

Clinical Importance

‒ Applications in Asian Health

• Future Directions

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Why do we care?

Revolutionary approach to cancer therapy

Effective and durable responses

Tolerable toxicity profile BUT

• Watch for late & long-term toxicities

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Weber et al J Clin Oncol 2017

Toxicities of Immune Checkpoint Inhibition

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NEUROLOGIC• Motor/sensory neuropathy

ENDOCRINE• Hypophysitis• Thyroiditis• Adrenal insufficiency• Diabetes

GASTROINTESTINAL• Diarrhea/colitis• Hepatitis• Pancreatitis

RHEUMATOLOGIC• Arthralgias/myalgias

DERMATOLOGIC• Rash• Pruritus• Vitiligo• SJS/TEN

PULMONARY• Pneumonitis

CARDIAC• Myocarditis

OCULAR• Uveitis/scleritis

Ipilimumab-induced Hypophysitis

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“The striking finding is diffuse enlargement of the pituitary which measures 1.3 cm in height, 1.3 cm AP and approximately 1.1 cm maximum transverse. The gland appears heterogeneous without discrete focal mass and bulges superiorly into the suprasellar cistern without definite compromise of the optic chiasm. No evidence of parasellar mass.”

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10/10/20178

Immune-related Adverse Events (irAEs)

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Managing iRAEs: General Principles

Patient education

Evaluate patients prior to infusions (basic labs, H&P)

General principles:

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Managing irAEs: General Principles

• Steroids

• Burst/quick taper

• 1-2 mg/kg, taper over 1 month

• Immunosuppression

• infliximab

• mycophenalate mofetil

• cyclophosphamide

• Referral to appropriate specialists

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Common Terminology Criteria for Adverse Events (CTCAE)Toxicity Grade 1 Grade 2 Grade 3 Grade 4Skin Covering <10%

body surface area (BSA)

Covering 10-30% BSA

Covering >30% BSA

More severe IV antibiotics, burn unit admission

Diarrhea Increase of <4 stools over baseline

Increase of 4-6 stools over baseline

Increase of ≥7 stools hospitalization indicated, incontinence

Life-threatening consequences, urgent intervention

Hepatotoxicity AST or ALT>ULN-3 x ULNorT. bili>ULN–1.5xULN

AST or ALT > 3-5 x ULN orT. bili >1.5–3xULN

AST or ALT >5-20 x ULN orT. bili>3–10xULN

AST or ALT >20 x ULN orT. bili>10xULN

Endocrine, pneumonitis

Asymptomatic Symptomatic Severe symptoms, hospitalization indicated

Life-threatening

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10/10/20179

Do Asians Get Melanoma?

YES!

• Clinically and genetically heterogeneous disease

• Predominance of acral lentiginous melanoma (ALM)

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Melanoma in the Asian Population

42-65% incidence of ALM in studies from Taiwan, China, South Korea, Singapore, Japan

• Contrast with 2-3% ALM incidence in Caucasian population

Presentation at later stage

Different risk factors: long-term physical stress, trauma

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Chang JWC et al, Melanoma Res 2004.Chi Z et al, BMC Cancer 2011.Roh MR et al, Yonsei Med 2010.Lee HY et al, Ann Acad Med Singapore 2012.Ishihara K et al, Int J Clin Oncol 2008.

Different Outcomes in Melanoma Subtypes with Anti-PD-1 Therapy

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Outline

Immunology 101

Cancer Immunotherapy

‒ Definition

‒ Non-specific vs Specific

‒ Mechanisms of Action

Clinical Importance

‒ Applications in Asian Health

Future Directions

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10/10/201710

FDA Approvals for PD-1/L1 Antibodies

Melanoma

Non-small cell lung cancer

Head and neck squamous cell carcinoma

Urothelial carcinoma

Renal cell carcinoma

Hodgkin lymphoma

Merkel cell carcinoma

Microsatellite instability high (MSI-H) colorectal cancer

Any MSI-H or dMMR (deficient mismatch repair) pediatric/adult solid tumor

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Somatic mutation frequency across human cancer types

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Lawrence et al, Nature 2013.

Identification of Other Checkpoints

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Chen and M

ellm

an, Immunity 2013.

Ongoing Investigation

Immune checkpoint inhibitors in other cancers

Novel combinations

Targeting other cells in tumor microenvironment

Biomarker research

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10/10/201711

Thank you!Katy.Tsai@ucsf.edu

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