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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