Releasing the Brakes on Tumor Immunity: Immune Checkpoint Blockade Strategies

Releasing the Brakes on Tumor Immunity: Immune Checkpoint Blockade Strategies Jason Muhitch, PhD MIR 509 October 1 st, 2014 Email: jason.muhitch@roswellpark.org 0

Holy Grail of Tumor Immunity 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 Realized in 1987 in a subset of RCC and melanoma patients treated with HD IL-2 Rosenberg, S et al. NEJM 1987 4/19/2006 9/19/2007 Schwaab et al. Clin Cancer Res 2009 RCC and Melanoma are the most responsive to state-of-the-art (checkpoint blockade, DC, adoptive transfer) and traditional (IL-2) immunotherapy

Holy Grail of Tumor Immunity Melanoma Following the lecture students will be able to: Discuss requirements for effective anti-tumor immune responses. Identify immunosuppressive elements that hinder responses. T cell Describe current immune-based treatments for malignancies. M Mikucki 3

Requirements for Effective Anti-Tumor Immune Responses Tumor Tumor Ag Soluble factors Dendritic cells Draining Lymph Node 1. T cell recognition of tumor Ags presented by DC 2. T cell Activation HEV Tumor vessel 3. T cell infiltration into lymph nodes & tumors 4. Lysis of tumor targets Tumor cell destruction CD8 effector T cells T cell expansion 4

Requirements for Effective Anti-Tumor Immune Responses Tumor Tumor Ag Soluble factors Dendritic cells Draining Lymph Node 1. T cell recognition of tumor Ags presented by DC 2. T cell Activation HEV Tumor vessel 3. T cell infiltration into lymph nodes & tumors 4. Lysis of tumor targets Tumor cell destruction CD8 effector T cells T cell expansion 5

Characterizing Tumor Immune Responses T cell recognition of tumor antigens Stage IV melanoma patients Speiser et al, Eur J Immunol. 2002 6

Characterizing Tumor Immune Responses Tumor sites are often characterized by poor T cell infiltration Human Melanoma (CD45/Hematoxylin) Tumor Limited CD8 infiltration correlates with poor prognosis in melanoma. Leukocytes Tumor Repasky and Hylander 7 Piras et al. Cancer. 2005

Tumor Immune Suppression Blocks Pathways that Promote T Cell-mediated Tumor Immunity 8

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 9

Removing Removing a Tumor s Tumor s Cloak Cloak of of Invisibility: Invisibility: Reversing Reversing Tumor Tumor Immunosuppression Immunosuppression Nature Medicine 18, 993 (2012) 10

Exhausted Effector T cells in the Tumor Microenvironment: Bringing a Knife to a Gun Fight Ahmadzadeh et al Blood 2009 11

RECIST Criteria: Response Evaluation Criteria in Solid Tumors Complete Response Partial Response Stable Disease Disappearance of all measurable tumors for more than 4 weeks >30% tumor size reduction of all lesions Small changes that do not meet above criteria Progressive Disease: >20% tumor size increase or appearance of new lesions 12

Antibody-mediated Therapies: PD-1 & PDL-1 PD-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 PDL-1 Roche, Genentech: MPDL320A Hamid et al, NEJM 2013 45% of patients progression free at 24 weeks. Patients with melanoma had a 29% response rate http://am.asco.org/daily-news 13

Tumors from Responders to Lambrolizumab Treatment Had Dense CD8 T Cell Infiltration Baseline Day 90 Hamid O et al. N Engl J Med 2013;369:134-144 14

Tumors from Responders to following Nivolumab Treatment Had Dense CD8 T Cell Infiltration Brahmer J R et al. JCO 2010;28:3167-3175 15

Vitiligo is Associated with Complete Response following Nivolumab Treatment Topalian SL et al. N Engl J Med 2012;366:2443-2454 16

Removing a Tumor s Cloak of Invisibility: Reversing Tumor Immunosuppression Yervoy (anti-ctla-4, ipilimumab) MHC 1 Ag TCR CD80/86 CD80/86 2 CD28 CTLA4 CD8 T c Bristol-Myers Squibb Anti-CTLA4 (Ipilimumab) 17

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. Bristol-Myers Squibb Associated with immune-mediated side effects. Colitis Dermatitis Vanneman et al Nature Rev Canc 2012 Hodi et al NEJM 2010 18

Objective Response Rates of Available Immunotherapy Options for RCC 50 Objective Response % 40 30 20 10 259 17 33 40 557 553 Treatment IL-2 Anti-PD-L1 Anti-PD-1 CTLA-4 Pazopanib Sunitinib 1 st enrolled Pt. 1986 2009 2008 2007 2008 2008 Klapper Cancer 2008 Brahmer NEJM 2013 Topalian NEJM 2012 Yang Immunoth 2007 Tyrosine Kinase Inhibitors Motzer NEJM2013

Objective Response Rates of Available Immunotherapy Options for RCC 50 Objective Response % 40 30 20 10 259 17 33 40 557 553 Treatment IL-2 Anti-PD-L1 Anti-PD-1 CTLA-4 Pazopanib Sunitinib 1 st enrolled Pt. 1986 2009 2008 2007 IL-2 has the greatest level of cytoxicity Klapper Cancer 2008 Brahmer NEJM 2013 Topalian NEJM 2012 Yang Immunoth 2007 and patient management 2008 2008 Motzer NEJM2013

Complete Response Rates of Available Immunotherapy Options for RCC 50 Complete Response % 40 30 20 10 259 17 33 40 557 553 Treatment IL-2 Anti-PDL-1 Anti-PD-1 CTLA-4 Pazopanib Sunitinib 1 st enrolled Pt. 1986 2009 2008 2007 2008 2008 Klapper Cancer 2008 Brahmer NEJM 2013 Topalian NEJM 2012 Yang Immunoth 2007 Tyrosine Kinase Inhibitors Motzer NEJM2013

Complete Response Rates of Available Immunotherapy Options for RCC Complete Response % 50 40 30 20 10 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) 259 17 33 40 557 553 Treatment IL-2 Anti-PDL-1 Anti-PD-1 CTLA-4 Pazopanib Sunitinib 1 st enrolled Pt. 2009 2008 2007 IL-2 remains Klapper Cancer the 2008 most Brahmer NEJM effective 2013 Topalian NEJM stand 2012 Yang alone Immunoth 2007 strategy to induce long term complete responses

Checkpoints to the Generation of Anti-Tumor Immunity: Strength in Numbers Tumor Tumor Ag Soluble factors Dendritic cells Draining Lymph Node 1. T cell recognition of tumor 2. T cell Activation HEV Tumor vessel 3. T cell infiltration into lymph nodes & tumors 4. Lysis of tumor targets Tumor cell destruction CD8 effector T cells T cell expansion 23

Improved Responses To Combined Immune Checkpoint Blockade Treatment (CTLA-4 + PD-1) Wolchok JD et al. N Engl J Med 2013;369:122-133 24

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 25

Dendritic Cell Vaccination Strategies to Improve Ex Vivo Culture into Dendritic Cells (IL4, GMCSF) Pulsing with Autologous Tumor Cell Lysate Purification of Monocytes Injection into Patient s Lymph Node 16% Progressive Disease 16% Complete Response Peripheral Blood Goal: Boost Anti-Tumor Immune- Response 33% Stable Disease 33% Partial Response N= 18

Heterogeneous Patient Responses in Clinical Trial 16% Progressive Disease 33% Stable Disease 16% Complete Response 33% Partial Response Complete Response Partial Response Disappearance of all measurable tumors for more than 4 weeks >50% tumor size reduction of all lesions Stable Disease <50% tumor size reduction and <25% tumor size increase N= 18 Progressive Disease: >25% tumor size increase or appearance of new lesions

Analysis of Patient samples from DC-Vaccine Trial Mo-3 Mo-2 Mo-1 CD16 CD14 Mo-3 monocytes from RCC patients show distinct gene expression from healthy donors Healthy control

Dendritic Cell Vaccinations: Orchestrating Immune Responses from the Battleground Palucka et al Nat Rev Cancer 2012 29

Dendritic Cell Vaccinations: Orchestrating Immune Responses from the Battleground Ongoing phase III clinical trial at RPCI (Dr. Schwaab) utilizing dendritic cell electroporated with tumor RNA for treatment of Renal Cell Carcinoma Palucka et al Nat Rev Cancer 2012 30

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 Di Lorenzo Nature Reviews Clinical Oncology 2011 31

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 32

Checkpoints to the Generation of Anti-Tumor Immunity: Strength in Numbers Tumor Tumor Ag Soluble factors Dendritic cells Draining Lymph Node 1. T cell recognition of tumor 2. T cell Activation HEV Tumor vessel 3. T cell infiltration into lymph nodes & tumors 4. Lysis of tumor targets Tumor cell destruction CD8 effector T cells T cell expansion 33