Releasing the Brakes on Tumor Immunity: Immune Checkpoint Blockade Strategies

Jason Muhitch, PhD MIR 509

October 1st, 2014 Email: jason.muhitch@roswellpark.org

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Exquisite specificity for target; limit collateral damage

Target non-resectable tumors

Systemic immunity; target tumors throughout the body

Long-lasting protection

Holy Grail of Tumor Immunity

Holy Grail of Tumor Immunity

Realized in 1987 in a subset of RCC and melanoma patients treated with HD IL-2

Rosenberg, S et al. NEJM 1987

RCC and Melanoma are the most responsive to state-of-the-art (checkpoint blockade, DC, adoptive transfer) and traditional (IL-2) immunotherapy

9/19/2007 4/19/2006

Schwaab et al. Clin Cancer Res 2009

Discuss requirements for effective anti-tumor immune responses.

Identify immunosuppressive elements that hinder responses.

Describe current immune-based treatments for malignancies.

Melanoma

T cell

M Mikucki

Following the lecture students will be able to:

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Holy Grail of Tumor Immunity

Requirements for Effective Anti-Tumor Immune Responses

HEV

Tumor Ag Soluble factors Dendritic cells

CD8 effector T cells

Tumor Draining Lymph Node

Tumor cell destruction

1. T cell recognition of tumor Ags presented by DC

2. T cell Activation 3. T cell infiltration into lymph

nodes & tumors

4. Lysis of tumor targets

Tumor vessel

T cell expansion

4

Requirements for Effective Anti-Tumor Immune Responses

HEV

Tumor Ag Soluble factors Dendritic cells

CD8 effector T cells

Tumor Draining Lymph Node

Tumor cell destruction

1. T cell recognition of tumor Ags presented by DC

2. T cell Activation 3. T cell infiltration into lymph

nodes & tumors

4. Lysis of tumor targets

Tumor vessel

T cell expansion

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Characterizing Tumor Immune Responses

T cell recognition of tumor antigens

Speiser et al, Eur J Immunol. 2002

Stage IV melanoma patients

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Limited CD8 infiltration correlates with poor prognosis in melanoma.

Piras et al. Cancer. 2005

Tumor sites are often characterized by poor T cell infiltration

Characterizing Tumor Immune Responses

Human Melanoma (CD45/Hematoxylin)

Tumor

Tumor

Leukocytes

Repasky and Hylander

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Tumor Immune Suppression Blocks Pathways that Promote T Cell-mediated Tumor Immunity

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Removing a Tumor’s Cloak of Invisibility: Overcoming Tumor Immunosuppression Antibody immune-based therapeutics (3 of top 10 2013

experimental cancer drugs) PD-1 Nivolumab (BMS-936558) (Bristol-Myers Squibb) Lambrolizumab (MK-3475) (Merck)

PDL-1 MPDL320A (Roche, Genentech)

CTLA-4 Yervoy (Merck)

Dendritic cell vaccinations

Adoptive transfer of tumor-specific T cells

10 Nature Medicine 18, 993 (2012)

Removing a Tumor’s Cloak of Invisibility: Reversing Tumor Immunosuppression Removing Tumor’s Cloak of Invisibility: Reversing Tumor Immunosuppression

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Ahmadzadeh et al Blood 2009

Exhausted Effector T cells in the Tumor Microenvironment: Bringing a Knife to a Gun Fight

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RECIST Criteria: Response Evaluation Criteria in Solid Tumors

Complete Response Disappearance of all measurable tumors for more than 4 weeks

Partial Response >30% tumor size reduction of all lesions

Stable Disease Small changes that do not meet above criteria

Progressive Disease:

>20% tumor size increase or appearance of new lesions

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Antibody-mediated Therapies: PD-1 & PDL-1

Bristol-Myers Squibb - BMS-936558 nivolumab Phase I clinical trial, advanced patients demonstrated: Cumulative response rates: 18% of non–small-cell lung, 28%

melanoma, and 27% renal-cell cancer patients. Durable responses observed in 20 out of 31 patients

Topalian et al, NEJM 2012

Merck - Lambrolizumab (MK-3475) In Phase I clinical trial, response rate of 38% in patients

with advanced melanoma

PD-1

Hamid et al, NEJM 2013

PDL-1

45% of patients progression free at 24 weeks. Patients with melanoma had a 29% response rate

http://am.asco.org/daily-news

Roche, Genentech: MPDL320A

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Tumors from Responders to Lambrolizumab Treatment Had Dense CD8 T Cell Infiltration

Hamid O et al. N Engl J Med 2013;369:134-144

Baseline Day 90

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Tumors from Responders to following Nivolumab Treatment Had Dense CD8 T Cell Infiltration

Brahmer J R et al. JCO 2010;28:3167-3175

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Vitiligo is Associated with Complete Response following Nivolumab Treatment

Topalian SL et al. N Engl J Med 2012;366:2443-2454

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Removing a Tumor’s Cloak of Invisibility: Reversing Tumor Immunosuppression

Bristol-Myers Squibb

Yervoy (anti-CTLA-4, ipilimumab)

CD8 Tc

MHC Ag

TCR

CD80/86

CD80/86

CD28

CTLA4

1

2

Anti-CTLA4 (Ipilimumab)

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Removing a Tumor’s Cloak of Invisibility: Reversing Tumor Immunosuppression

Yervoy (anti-CTLA-4, ipilimumab) Approved by FDA as first-line or second-line treatment for advanced melanoma.

Blocks inhibitory signal for activated T cells.

Enhances survival & durable responses (>2.5 y) in 15- 20% of patients.

Response can be delayed.

Associated with immune-mediated side effects. Colitis Dermatitis

Vanneman et al Nature Rev Canc 2012 Hodi et al NEJM 2010

Bristol-Myers Squibb

Objective Response Rates of Available Immunotherapy Options for RCC

Obj

ectiv

e R

espo

nse

%

20

30

40

50

1986

IL-2

2009

Anti-PD-L1

Klapper Cancer 2008

Treatment

1st enrolled Pt.

Brahmer NEJM 2013

2008

Anti-PD-1

Topalian NEJM 2012

CTLA-4

2007

Yang Immunoth 2007

Pazopanib

259

17

33

40

557 553

Sunitinib

Motzer NEJM2013

2008 2008

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Tyrosine Kinase Inhibitors

Objective Response Rates of Available Immunotherapy Options for RCC

1986 2009

Klapper Cancer 2008

Treatment

1st enrolled Pt.

Brahmer NEJM 2013

2008

Topalian NEJM 2012

2007

Yang Immunoth 2007 Motzer NEJM2013

2008 2008

IL-2 has the greatest level of cytoxicity and patient management

20

30

40

50

IL-2 Anti-PD-L1 Anti-PD-1 CTLA-4 Pazopanib

259

17

33

40

557 553

Sunitinib

10

Obj

ectiv

e R

espo

nse

%

Complete Response Rates of Available Immunotherapy Options for RCC

1986 1st enrolled Pt. 2009 2008 2008

Klapper Cancer 2008 Brahmer NEJM 2013 Topalian NEJM 2012 Yang Immunoth 2007

2008 2007

IL-2 CTLA-4 Treatment Anti-PDL-1 Anti-PD-1 Pazopanib Sunitinib

40

259

17

33 557 553

20

30

40

50

10

Com

plet

e R

espo

nse

%

Motzer NEJM2013

Tyrosine Kinase Inhibitors

1st enrolled Pt. 2009

Klapper Cancer 2008 Brahmer NEJM 2013 Topalian NEJM 2012 Yang Immunoth 2007

2008 2007

IL-2 remains the most effective stand alone strategy to induce long term complete responses

More than 80% of complete responders are still disease free > 2 years post treatment Rosenberg et al Annals of Surgery 1998 Klapper et al Cancer 2008 Muhitch and Schwaab Immunotherapy (In press)

Complete Response Rates of Available Immunotherapy Options for RCC

IL-2 CTLA-4 Treatment Anti-PDL-1 Anti-PD-1 Pazopanib Sunitinib

40

259

17

33 557 553

20

30

40

50

10

Com

plet

e R

espo

nse

%

Checkpoints to the Generation of Anti-Tumor Immunity: Strength in Numbers

HEV

Tumor Ag Soluble factors Dendritic cells

CD8 effector T cells

Tumor Draining Lymph Node

Tumor cell destruction

1. T cell recognition of tumor 2. T cell Activation 3. T cell infiltration into lymph

nodes & tumors

4. Lysis of tumor targets Tumor vessel

T cell expansion

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Improved Responses To Combined Immune Checkpoint Blockade Treatment (CTLA-4 + PD-1)

Wolchok JD et al. N Engl J Med 2013;369:122-133

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Boosting Tumor Immune Responses

Antibody immune-based therapeutics (3 of top 10 experimental cancer drugs) PD-1 Nivolumab (BMS-936558) (Bristol-Myers Squibb) Lambrolizumab (MK-3475) (Merck)

PDL-1 MPDL320A (Roche, Genentech)

CTLA-4 Yervoy (Merck)

Dendritic cell vaccinations

Adoptive transfer of tumor-specific T cells

16% Progressive Disease

16% Complete Response

33% Stable Disease

33% Partial Response

Purification of Monocytes

Ex Vivo Culture into Dendritic Cells (IL4, GMCSF)

Peripheral Blood

Pulsing with Autologous Tumor Cell Lysate

Goal: Boost Anti-Tumor Immune-Response

Injection into Patient’s Lymph Node

N= 18

Dendritic Cell Vaccination Strategies to Improve

Heterogeneous Patient Responses in Clinical Trial

16% Progressive Disease

16% Complete Response

33% Stable Disease

33% Partial Response

Complete Response Disappearance of all measurable tumors for more than 4 weeks

Partial Response >50% tumor size reduction of all lesions

Stable Disease <50% tumor size reduction and <25% tumor size increase

Progressive Disease:

>25% tumor size increase or appearance of new lesions N= 18

Analysis of Patient samples from DC-Vaccine Trial

Mo-1

Mo-2

Mo-3

Healthy control

Mo-3 monocytes from RCC patients show distinct gene expression from healthy donors

CD14

CD16

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Dendritic Cell Vaccinations: Orchestrating Immune Responses from the Battleground

Palucka et al Nat Rev Cancer 2012

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Dendritic Cell Vaccinations: Orchestrating Immune Responses from the Battleground

Palucka et al Nat Rev Cancer 2012

Ongoing phase III clinical trial at RPCI (Dr. Schwaab) utilizing dendritic cell electroporated with tumor RNA for treatment of Renal Cell Carcinoma

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Sipuleucel-T

FDA approved for treatment of metastatic castrate resistant prostate cancer

Induces antibody and T cell responses

Overall 4 month prolonged median survival benefit

Few objective biological responses

Di Lorenzo Nature Reviews Clinical Oncology 2011

Kantoff et al. N Engl J Med. 2010

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Sipuleucel-T

FDA approved for treatment of metastatic castrate resistant prostate cancer

Induces antibody and T cell responses

Overall 4 month prolonged median survival benefit

Few objective biological responses Kantoff et al. N Engl J Med. 2010

Checkpoints to the Generation of Anti-Tumor Immunity: Strength in Numbers

HEV

Tumor Ag Soluble factors Dendritic cells

CD8 effector T cells

Tumor Draining Lymph Node

Tumor cell destruction

1. T cell recognition of tumor 2. T cell Activation 3. T cell infiltration into lymph

nodes & tumors

4. Lysis of tumor targets Tumor vessel

T cell expansion

33