Cancer and the immune system: can we beat cancer at its own game?

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1 Cancer and the immune system: can we beat cancer at its own game? Andrew R. Haas, MD, PhD Assistant Professor of Medicine University of Pennsylvania Medical Center Philadelphia, Pa

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6 Why can t immune cells kill cancer? Production of suppressing factors by Cancer cells Supporting tissue (stromal cells) of the cancer Immune system itself Soluble factors TGF-beta, VEGF, prostaglandins (cox-2) Immune factors Regulatory T-cells, tumor-infiltrating macrophages

7 Cancer Immunotherapy Strategies Ex vivo: Tumor vaccines In situ: Generate antigens by killing the cancer Suicide genes Oncolytic virotherapy Transfer of immune stimulating genes Blockade of suppressive factor production or action Manipulate antigens to our advantage Combination of the above

8 Enhanced Ag presentation by appropriately activated presenting cells Immunotherapy Paradigm (Drew Pardoll) Expansion of Memory/ Effector Cells Blockade of Immunologic Check Points Enhanced traffic of tumor specific T- cells to tumors and metastases Ad.IFN- Additional Rx Anti-CTLA4 Surgery COX-2 Inhibitors Chemotherapy TGF- Inhibitors

9 What makes mesothelioma amenable to immunotherapy? Immunogenic tumor based on animal models Accessible body cavities involved Less likely to have extensive bulk of cancer and metastases Most therapies marginally effective

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11 Intratumoral VV-IL-2 Phase I Clinical Trial Six patients with treatment-resistant MPM received intratumoral (i.t.) injection Persistent IL-2 expression T-cell infiltrate detected in 50% of tumor biopsies No significant toxicities, contact infection, or tumor regressions Robinson, BW et al. J Immunother 1998 Mukherjee, S et al. Cancer Gene Ther, 2000

12 IFN- Gene Delivery - Biologic Thesis Direct inhibition of tumor cell proliferation and survival Activate anti-tumor immune response by activating natural killer cells, macrophages and cytotoxic T lymphocytes Potential antiangiogenic activity Inhibition of Tumor Cell Growth Tumor Cell Death

13 Phase I trial of single dose IFN- Technically feasible Well tolerate with minimal toxicity Intrapleural IFN-β expression Select cellular and humoral immune responses detected Anecdotal CT/PET responses

14 Pt 107 Pre/Post 18-FDG PET Scans: Mixed Response Left Apical Lesions Left Basilar Lesion PRE POST Complete Metabolic Response in Left Basilar Pleural Lesion Post Ad.IFN-ß

15 Phase I Trial of Repeat Dose Ad.IFN-β in Mesothelioma 1st Dose INFbeta Levels: 2 dose Trial IFNbeta- ng/ml nd Dose Days after 1st Gene Transfer Pt 203 Pt 205 Pt 210 Pt 211 Pt 212 Pt 213 Pt 214 Pt 215

16 Pt FDG PET Pre/Post Pre- Ad.IFN Beta Post- Ad.IFN Beta

17 Rationale for Mesothelin- Directed Immunotherapy Mesothelin Overexpression in Cancer Over-expressed mesothelioma Limited expression in other tissues Patient benefit correlated with Mesothelin-specifi T cell responses Mesothelin-specific responses observed in long-term survivors only No autoimmunity observations Mesothelin-specific T cells kill human pancreatic tumor cells in vitro Argani, 2001, Clin Cancer Res, 7:3862 Hassan, 2004, Clin Cancer Res, 10:3937 Jaffee, 2001 JCO, 19:145 Thomas, 2004 J Ex Med, 200:297

18 Mechanism of Mesothelin Immunotoxin Action Zhang et al. PNAS, 2007

19 Anti-Mesothelin Antibody SS1P in Phase I Clinical Trial in Malignant Mesothelioma

20 MORAB-009 Phase II Clinical Trial: Alimta/Cisplatin + Anti-Mesothelin MAb Open-label, single arm Phase II trial. Sponsored by Morphotek, Inc. MORAB-009 Given on days 1 and 8 of each treatment cycle in concert with Alimita/Cisplatin [B12/Folate] Primary endpoint: Progression-free survival using the EORTC modified RECIST criteria

21 What can patients do to help their immune system? Google search mesothelioma and immune system 309,000+ hits 4 th hit alternative therapy Does alternative medicine have a role? Possibly Meditation Visual imagery Acupuncture Yoga Probably not Herbal remedies Mega vitamins Macro diets Chelation and other IVs Eat a well balanced diet and get rest

22 Final thoughts Promising early data on some benefit of immunotherapy in mesothelioma Next step multimodality therapy Immunotherapy Chemotherapy Radiation therapy Surgery

23 UPenn Thoracic Oncology Gene Therapy Group: Laboratory Director: Steven M. Albelda, M.D. Clinical Director: Daniel H. Sterman, M.D. Immunoblotting: Dr. Jing Sun, Luana Pereira Neutralizing Abs: Veena Kapoor, Luana Pereira CTL tetramer assays: Elaina Lord, Drs. Bob Vonderheide. Mesothelin ELISA: Drs. Mitch Ho and Ira Pastan. Cell Culture: Richard Carroll, Ph.D. Cytokine Assays: Jennifer Brown and Dr. Michael Parr Patient Care Drs. Colin Gillespie, Andrew Haas, Jonathan Puchalski, Steven Leh Nurse Coordinator: BiogenIDEC: Trial Support Funding: Adriana Recio, R.N. Murine/Human Vectors, Clinical NIH/NCI PO1 CA66726