Dr. Patrick Hwu presents the latest information on immunotherapies for melanoma at the MRF's Patient Symposium at MD Anderson Cancer Center on January 31, 2015.

1. Melanoma Immunotherapy
Patrick Hwu, MD
Professor and Chairman
Melanoma Medical Oncology
Saturday, January 31, 2015

2. If Not Removed at an Early Stage
Melanoma Can Spread Throughout the Body
Liver

3. 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

4. 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

5. New Immunotherapies for Melanoma
• Cancer Vaccines
− Peptides
− Dendritic Cells
− Recombinant viruses
• Antibodies
− Anti-CTLA-4
− Anti-PD-1
• T-cells
− TIL
− CARs
5

6. Cytotoxic T-lymphocytes Can Recognize
and Kill Tumor Cells
(From UVA)
6

7. Vaccines Stimulate the Proliferation
of T-cells In Vivo
Mature
Dendritic Cells
T-cells

8. 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

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

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

11. Responses Following Vaccination with
Resiquimod
Baseline After vaccination,
Resiquimod

12. New Immunotherapies for Melanoma
• Cancer Vaccines
− Peptides
− Dendritic Cells
− Recombinant viruses
• Antibodies
− Anti-CTLA-4
− Anti-PD-1
• T-cells
− TIL
− CARs
12

13. Immune
system
brakes on
Cancer Cells
Growing
Immune Cells Have “Brakes” So
They Don’t Attack Normal Tissues

14. Cancer Cells
under attack
Immune system
brakes removed
with 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

15. 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 2010
15

16. 16
Long Term Survival of Patients with Metastatic Melanoma
Treated with anti-CTLA-4 at Surgery Branch, NCI

17. 17 Year Melanoma Survivor!
Terry Mueller

18. 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

19. 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 2012
19

20. Baseline After 2 months After 6 months
Clinical Response to anti-PDL-1 in a
Patient with Metastatic Melanoma
20

21. New Immunotherapies for Melanoma
• Cancer Vaccines
− Peptides
− Dendritic Cells
− Recombinant viruses
• Antibodies
− Anti-CTLA-4
− Anti-PD-1
• T-cells
− TIL
− CARs
21

22. Adoptive Cell Therapy (ACT)
with Antigen Specific T-cells
Surgical
Removal of
Cancer Nodule
Single Cell
Suspension
Incubated with IL-2
T Cells
Proliferate
Cancer
Cells
Die
T Cells
IL-2
22

23. Before TIL Infusion
After TIL Infusion
Clinical Response following Lymphodepletion +
T-lymphocyte Infusion
23

24. Response to TIL Therapy
24
Aug 7, 2013May 18,
2010
Source: Patrick Hwu
MDACC Prot # 2004-0069 24

25. 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. 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
ProportionSurviving

27. 7 Year Melanoma Survivor!
Trey Rood

28. Moving Beyond Single Agent
Immune Therapy
• Combination Immunotherapy
– Antibody plus Antibody
– Antibody plus T-cells
• Targeted Therapy and Immunotherapy
28

29. Survival of B-16-bearing Mice
Vaccinated with Fvax + Antibody
29
Curran … Allison. PNAS 2010

30. 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

31. Best Responses in All Evaluable Patients
in Sequenced Cohorts
31Wolchok, NEJM, 2013
ChangeinTargetfromBaseline(%)
Patients

32. 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 / 53
Censored
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

33. I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673
T-cell Targets for Immunoregulatory
Antibody Therapy

34. I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673
T-cell Targets for Immunoregulatory
Antibody Therapy

35. 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. 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 Research
Melanoma 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 Hawke
GI Team:
− Anirban Maitra
− Bob Wolff
− Mike Overman
− Scott Kopetz
− Aaron Schuneman
− Jason Fleming
TIL Lab:
− Marie Andre Forget
− OJ Fulbright
− Audrey Gonzalez
− Valentina Dumitru
− Arly Wahl
− Esteban Flores
− Shawne Thorsen
Adelson Medical Research Foundation
NCI
GSK
Prometheus
Roche/Genenteich
Weizman Institute of Science – Zelig Eshhar
Ella Institute of Melanoma, Sheba Medical
Center, Tel Hashomer, Isreal
MDACC
Melanoma Moon Shot
Development Office
Ton Schumacher