Melanoma Immunotherapy

Patrick Hwu, MD

Professor and Chairman

Melanoma Medical Oncology

Saturday, January 31, 2015

If Not Removed at an Early Stage

Melanoma Can Spread Throughout the Body

Liver

Agents that were FDA Approved for

Metastatic Melanoma Prior to 2011

• Dacarbazine (DTIC) gained FDA

approval in May of 1975.

• IL-2 as an immunotherapy was

approved for a cancer treatment

strategy in 1992 by the FDA.

3

More Recent Agents that have been

FDA Approved for Metastatic Melanoma

• Vemurafenib (Zelboraf) for BRAF mutant late-stage melanoma

- August 17, 2011.

• Ipilimumab (MDX-010/Yervoy) for late-stage melanoma that

has spread or cannot be removed by surgery - March 2011.

• Dabrafenib (Talfinlar) for BRAF mutant metastatic melanoma

that cannot be surgically removed – May 2013.

• Tremetinib (Mekinist) for metastatic melanoma that cannot be

surgically removed – May 2013.

• Pembrolizumab (Keytruda) for advanced melanoma that no

longer responds to other drugs - September 2014.

• Nivolumab (Opdivo) for advanced melanoma that no longer

responds to other drugs – December 2014.4

New Immunotherapies for Melanoma

• Cancer Vaccines

− Peptides

− Dendritic Cells

− Recombinant viruses

• Antibodies

− Anti-CTLA-4

− Anti-PD-1

• T-cells

− TIL

− CARs5

Cytotoxic T-lymphocytes Can Recognize

and Kill Tumor Cells

(From UVA)

6

Vaccines Stimulate the Proliferation

of T-cells In Vivo

Mature

Dendritic Cells

T-cells

Treatment Schema: 2-Arm Randomized Study

for Patients with Metastatic Melanoma

IL-2

IL-2 Plus Vaccine

Primary Endpoint:

Clinical Response

8

Schwartzentruber DJ…Hwu P. N Engl J Med. 2011 Jun 2;364(22):2119-27

More Clinical Responses were Seen in

Patients Receiving IL-2 + Vaccine ( P = 0.022)

0

5

10

15

20

25

IL-2 IL-2 Plus Vaccine

9.7%

22.1%

9Schwartzentruber DJ…Hwu P. N Engl J Med. 2011 Jun 2;364(22):2119-27

Progression Free Survival is Enhanced

in Patients Receiving IL-2 + Vaccine

Median Survival months (95% CI)

IL-2 Alone: 1.6 (1.5-1.8)

IL-2+gp100: 2.9 (1.7-4.5)

p value: 0.01

Median Survival months (95% CI)

IL-2 Alone: 1.6 (1.5-1.8)

IL-2+gp100: 2.9 (1.7-4.5)

p value: 0.01

Median Survival months (95% CI)

IL-2 Alone: 1.6 (1.5-1.8)

IL-2+gp100: 2.9 (1.7-4.5)

10Schwartzentruber DJ…Hwu P. N Engl J Med. 2011 Jun 2;364(22):2119-27

Responses Following Vaccination with

Resiquimod

Baseline After vaccination,

Resiquimod

New Immunotherapies for Melanoma

• Cancer Vaccines

− Peptides

− Dendritic Cells

− Recombinant viruses

• Antibodies

− Anti-CTLA-4

− Anti-PD-1

• T-cells

− TIL

− CARs12

Immune system brakes on

Cancer Cells Growing

Immune Cells Have “Brakes” So

They Don’t Attack Normal Tissues

Cancer Cells under attack

Immune system brakes removedwith anti-CTLA-4 or anti-PD-1

T-Cells

Recently Drugs Have Been Developed

To Release The Brakes on Immune Cells

To Allow Them to Better Attack Cancer Cells

anti-CTLA-4 (Ipilimumab) Increases Progression Free Survival

and Overall Survival Compared to Vaccine Alone

for Patients with Metastatic Melanoma

Hodi et al. N Engl J Med 201015

16

Long Term Survival of Patients with Metastatic Melanoma

Treated with anti-CTLA-4 at Surgery Branch, NCI

17 Year Melanoma Survivor!

Terry Mueller

18

Receptor-ligand Pairs that Play a Role

in Regulating T-cell Function

Adapted from Immunology Letter 128:89-97, 2011

TNF-TNFR familyB7-CD28 family Additional molecules

MDACC Melanoma Moonshot

Durable Responses are Seen in Patients with Metastatic

Melanoma Treated with anti-PD1 Antibody

Phase I

Response

Rate

30-40%

Topalian et al. NEJM 201219

Baseline After 2 months After 6 months

Clinical Response to anti-PDL-1 in a

Patient with Metastatic Melanoma

20

New Immunotherapies for Melanoma

• Cancer Vaccines

− Peptides

− Dendritic Cells

− Recombinant viruses

• Antibodies

− Anti-CTLA-4

− Anti-PD-1

• T-cells

− TIL

− CARs21

Adoptive Cell Therapy (ACT)

with Antigen Specific T-cellsSurgical

Removal of

Cancer Nodule

Single Cell

Suspension

Incubated with IL-2

T Cells

Proliferate

Cancer

Cells

Die

T Cells

IL-2

22

Before TIL Infusion

After TIL Infusion

Clinical Response following Lymphodepletion +

T-lymphocyte Infusion

23

Response to TIL Therapy

24Aug 7, 2013May 18,

2010

Source: Patrick Hwu

MDACC Prot # 2004-0069 24

Clinical Response Data from

MDACC TIL Clinical Trial

Best overall response:

*Some patients are still undergoing clinical response

Number of

patients CR* PR* Total

71 3 (4%) 29(41%) 32 (45%)

Update to data published in

Clin Cancer Res 18: 6758-6770, 2012

Radvanyi … Hwu 25

26

Long Term Survival of Patients with Metastatic Melanoma

Treated at MD Anderson with TIL

Source: Roszik J and Bernatchez C - UT MD Anderson, Melanoma Research

(n = 79)

Median Survival = 671 days

Median Follow-up = 1323 days

Survival Time in Days

Pro

po

rtio

n S

urv

ivin

g

7 Year Melanoma Survivor!

Trey Rood

Moving Beyond Single Agent

Immune Therapy

• Combination Immunotherapy

– Antibody plus Antibody

– Antibody plus T-cells

• Targeted Therapy and Immunotherapy

28

Survival of B-16-bearing Mice

Vaccinated with Fvax + Antibody

29Curran … Allison. PNAS 2010

Computed Tomographic (CT) Scans of the Chest Showing

Tumor Regression in a Patient Who Received the

Concurrent Regimen of Nivolumab and Ipilimumab

Wolchok, NEJM, 2013

Pretreatment 12 weeks

A 52-year-old patient presented with extensive nodal and visceral disease

Baseline LDH was elevated (2.3 x ULN); symptoms included nausea and vomiting

Within 4 wk, LDH normalized and symptoms resolved

At 12 wk, there was marked reduction in all areas of Weeks since treatment initiation

disease as shown

30

Best Responses in All Evaluable Patients

in Sequenced Cohorts

31Wolchok, NEJM, 2013

Change in T

arg

et fr

om

Baselin

e (

%)

Patients

Patients at Risk

1 mg + 3 mg

All concurrent

17

53

16

47

16

36

14

29

10

19

5

10

3

7

2

4

2

4

1

3

0

1

0

1

0

0

n=17

n=53

Preliminary Survival of Patients Treated

with Ipilimumab + Nivolumab

Months

9 / 53Censored

All concurrent regimen

1 mg/kg nivolumab + 3 mg/kg ipilimumab

Died/Treated

2 / 17

1-year Survival

82%

95%CI (69.0%;94.4%)

Wolchok, Hodi, BMS

I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673

T-cell Targets for Immunoregulatory

Antibody Therapy

I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673

T-cell Targets for Immunoregulatory

Antibody Therapy

Potential Combinations for Clinical Trials

35

Immune Agents anti-CTLA-4

anti-PD-1

anti-PDL1

anti-41BB

anti-KIR

anti-CD4OL

anti-OX4O

Vaccines

T-cells

Targeted Agents BRAFi

MEKi

CDK4i

PI3Ki

AKTi

36

Acknowledgements

Preclinical Data and Laboratory Endpoints– Weiyi Peng– Shruti Malu– Rina Mbofung– Jodi McKenzie– Leila Williams– Chengwen Liu– Chunyu Xu– Zhe Wang– Donald Sakellariou-Thompson– Krit Ritthipichai

– Mike Davies

– Jen Wargo– Zac Cooper

– Tim Heffernan

– Cassian Yee– Jungsun Park

– Willem Overwijk

– Scott Woodman

– Chantale Bernatchez– Cara Haymaker– Geok Choo Sim– Caitlin Creasy– Rene Tavera

– Laszlo Radvanyi– Luis Vence

– Gordon Mills– Liz Grimm– Waun Ki Hong

Clinical ResearchMelanoma Medical Oncologists:

– Roda Amaria

– Wen Jen Hwu

– Adi Diab

– Isabella Glitza

– Sapna Patel

Surgeons:

– Jeff E. Lee

– Merrick Ross

– Jeff Gershenwald

– Richard Royal

– Anthony Lucci

– Janice Cormier

– W. Hofstetter

Pathologists:

– Victor Prieto

– Carlos Torres Cabala

– Michael Tetzlaff

– Doina Ivan

Research Nurses:

– Anna Vardeleon

– Suzanne Cain

– Portia Velasquez

– Vruti Patel

GMP Lab:

– EJ Shpall

– Enrique Alvarez

IND Office

Linda Duggan

Peptide Analysis:– Greg Lizee– Amjad Talukder– Jason Roszik– David HawkeGI Team:− Anirban Maitra− Bob Wolff− Mike Overman− Scott Kopetz− Aaron Schuneman− Jason FlemingTIL Lab:− Marie Andre Forget

− OJ Fulbright− Audrey Gonzalez− Valentina Dumitru− Arly Wahl− Esteban Flores− Shawne Thorsen

Adelson Medical Research FoundationNCIGSKPrometheusRoche/GenenteichWeizman Institute of Science – Zelig EshharElla Institute of Melanoma, Sheba Medical

Center, Tel Hashomer, IsrealMDACCMelanoma Moon ShotDevelopment Office

Ton Schumacher