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Melanoma Immunotherapy - Dr. Patrick Hwu

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3 di 36 25/10/2016 19:49

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

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Melanoma Immunotherapy - Dr. Patrick Hwu

1. Melanoma Immunotherapy Patrick Hwu, MD Professor and Chairman Melanoma Medical

Oncology Saturday, January 31, 2015

1.

2. If Not Removed at an Early Stage Melanoma Can Spread Throughout the Body Liver2.

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

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

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

5.

6. Cytotoxic T-lymphocytes Can Recognize and Kill Tumor Cells (From UVA) 66.

7. Vaccines Stimulate the Proliferation of T-cells In Vivo Mature Dendritic Cells T-cells7.

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

8.

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

9.

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

10.

11. Responses Following Vaccination with Resiquimod Baseline After vaccination, Resiquimod11.



12.

13. Immune system brakes on Cancer Cells Growing Immune Cells Have “Brakes” So They Don’t13.


4 di 36 25/10/2016 19:49

FDA approval in May of 197...

More Recent Agents that have been FDA Approved for Metastatic Melanoma • Vemurafenib (Zelboraf)

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

14.

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

15.

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

Surgery Branch, NCI

16.

17. 17 Year Melanoma Survivor! Terry Mueller17.

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

18.

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

19.

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

Metastatic Melanoma 20

20.



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

22.

23. Before TIL Infusion After TIL Infusion Clinical Response following Lymphodepletion +

T-lymphocyte Infusion 23

23.

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

2004-0069 24

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

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

26.

27. 7 Year Melanoma Survivor! Trey Rood27.

28. Moving Beyond Single Agent Immune Therapy • Combination Immunotherapy – Antibody plus

Antibody – Antibody plus T-cells • Targeted Therapy and Immunotherapy 28

28.

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

2010

29.

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

30.

31. Best Responses in All Evaluable Patients in Sequenced Cohorts 31Wolchok, NEJM, 2013

ChangeinTargetfromBaseline(%) Patients

31.

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

32.

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

Immunoregulatory Antibody Therapy

33.

34. I Mellman et al. Nature 480, 480-489 (2011) doi:10.1038/nature10673 T-cell Targets for34.


5 di 36 25/10/2016 19:49

for BRAF mutant late-stage...

New Immunotherapies for Melanoma • Cancer Vaccines − Peptides − Dendritic Cells − Recombinant


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

35.

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

36.

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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

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Vaccine Primary Endpoint: Cl...

More Clinical Responses were Seen in Patients Receiving IL-2 + Vaccine ( P = 0.022) 0 5 10 15 20 25

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IL-2 IL-2 Plus Vaccine...

Progression Free Survival is Enhanced in Patients Receiving IL-2 + Vaccine Median Survival months

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10 di 36 25/10/2016 19:49

(95% CI) IL-2 Alone: 1.6...

Responses Following Vaccination with Resiquimod Baseline After vaccination, Resiquimod


11 di 36 25/10/2016 19:49




12 di 36 25/10/2016 19:49

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

Normal Tissues


13 di 36 25/10/2016 19:49

Cancer Cells under attack Immune system brakes removed with anti-CTLA-4 or anti-PD-1 T-Cells

Recently Drugs Have Been Deve...


14 di 36 25/10/2016 19:49

anti-CTLA-4 (Ipilimumab) Increases Progression Free Survival and Overall Survival Compared to

Vaccine Alone for Patients w...


15 di 36 25/10/2016 19:49

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

Branch, NCI


16 di 36 25/10/2016 19:49

17 Year Melanoma Survivor! Terry Mueller

18 Receptor-ligand Pairs that Play a Role in Regulating T-cell Function Adapted from Immunology Letter


17 di 36 25/10/2016 19:49

128:89-97, 2011 TNF...

MDACC Melanoma Moonshot Durable Responses are Seen in Patients with Metastatic Melanoma


18 di 36 25/10/2016 19:49

Treated with anti-PD1 Antibody Pha...

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


19 di 36 25/10/2016 19:49

Melanoma 20



20 di 36 25/10/2016 19:49


Adoptive Cell Therapy (ACT) with Antigen Specific T-cells Surgical Removal of Cancer Nodule Single


21 di 36 25/10/2016 19:49

Cell Suspension Incubat...

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


22 di 36 25/10/2016 19:49

Infusion 23

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


23 di 36 25/10/2016 19:49

24

Clinical Response Data from MDACC TIL Clinical Trial Best overall response: *Some patients are still


24 di 36 25/10/2016 19:49

undergoing clinical r...

26 Long Term Survival of Patients with Metastatic Melanoma Treated at MD Anderson with TIL Source:


25 di 36 25/10/2016 19:49

Roszik J and Bernatchez...

7 Year Melanoma Survivor! Trey Rood


26 di 36 25/10/2016 19:49

Moving Beyond Single Agent Immune Therapy • Combination Immunotherapy – Antibody plus Antibody

– Antibody plus T-cells • T...


27 di 36 25/10/2016 19:49

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

Computed Tomographic (CT) Scans of the Chest Showing Tumor Regression in a Patient Who Received


28 di 36 25/10/2016 19:49

the Concurrent Regimen of ...

Best Responses in All Evaluable Patients in Sequenced Cohorts 31Wolchok, NEJM, 2013


29 di 36 25/10/2016 19:49

ChangeinTargetfromBaseline(%) 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


30 di 36 25/10/2016 19:49

n=17 n=53 Preli...

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


31 di 36 25/10/2016 19:49


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


32 di 36 25/10/2016 19:49


Potential Combinations for Clinical Trials 35 Immune Agents anti-CTLA-4 anti-PD-1 anti-PDL1


33 di 36 25/10/2016 19:49

anti-41BB anti-KIR ...

36 Acknowledgements Preclinical Data and Laboratory Endpoints – Weiyi Peng – Shruti Malu – Rina


34 di 36 25/10/2016 19:49

Mbofung – Jodi McKenzie – ...

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