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Immunotherapy Update for Ovarian Cancer


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Dr. Maurie Markman, President of Science and Medicine at Cancer Treatment Centers of America, shares his expertise on the latest developments in immunotherapy for ovarian cancer.

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Immunotherapy Update for Ovarian Cancer

  1. 1. Immunotherapy in the Management of Ovarian Cancer Maurie Markman, M.D. President, Medicine & Science Cancer Treatment Centers of America Clinical Professor of Medicine, Drexel University College of Medicine
  2. 2. Historical Perspective • Relationship between infection and cancer regression noted by at least the 18th century • Coley’s Toxin (1891) – case studies • Retrospective experiences with regression of cancer following post-operative infections (empyema) • Very rare case reports of regression of metastatic cancer following surgical removal of primary lesion (e.g., melanoma; renal cell)
  3. 3. Historical Perspective • Cancer recognized to occur in locations of chronic infection/inflammation (“scar” lung cancer) • Immune infiltrates commonly observed adjacent to tumors (positive or negative impact???) • Increased risk of cancer in individuals with “compromised immune systems” – Induced chronic immunosuppression to prevent graft rejection (e.g., renal, cardiac) – HIV infection
  4. 4. Immunotherapy: Vaccination (Cancer Prevention) • Immunize against infectious pathogens known to be related to subsequent development of cancer – Vaccine against hepatitis virus • Infection/inflammation leading to fibrosis/scaring and subsequent hepatocellular carcinoma – Vaccine against HPV • Prevent incorporation of viral genome into epithelial DNA responsible for > 99% of all cancers of the cervix and a large percentage of cancers of head & neck, anus, and vagina/vulva
  5. 5. Immunotherapy: Stimulation • Goal: Boost the immune system • High dose Interleukin-2 (melanoma) • Ex vivo manipulation of T-cells infused back into cancer patients • Very limited success – but highly provocative data related to small number of long-term disease- free survivors (5-10 years with metastatic melanoma) –S. Rosenberg, et al (NCI) • CAR-T cells (to date: hematologic malignancies)
  6. 6. Immunotherapy: Inhibit “Immune Blockade” • “Checkpoint” Inhibitors – “Release the brake on the recognition of the cancer as being foreign” • CTLA-4 (Ipilimumab) • Anti-PD-1 antibody (pembrolizumab, nivolumab) • Anti-PD-L1 antibody (atezolizumab)
  7. 7. Immunotherapy: Inhibit “Immune Blockage” • Documented clinical efficacy in multiple tumor types (solid and liquid cancers) based on both randomized and non-randomized experiences – melanoma, lung cancer, renal cell cancer, bladder cancer, head & neck cancers, chemotherapy- refractory lymphomas – (preliminary evidence for efficacy in a number of additional cancers with results of more definitive trials pending)
  8. 8. Immunotherapy: Inhibit “Immune Blockade” • Toxicity profile – Unique – immune-related side effects (activation of T-cells and ‘targeting’ of normal tissue) – combination immunotherapy heightened risk – Gastrointestinal (colitis) – Diabetes – Cardiac (“myocarditis”) – Hematologic – Pneumonitis
  9. 9. Solid Rationale for Immune Targeting in Ovarian Cancer • CD3+ tumor-infiltrating T cells correlate with improved survival • Immunosuppressive regulatory T cells found to be associated with inferior survival • Pre-clinical identification of potential tumor- associated antigens (CA-125; folate receptor) • Ovarian cancer patients not inherently immunocompromised • Relatively long-survival and time away from chemotherapy – favorable factors to permit an immune response
  10. 10. Clinical Experience (to date) • Adoptive cell therapy – Small 1990’s trial: Improved 3-year survival with ACT) • Antibody therapy (Cetuximab; Bevacizumab) • Immune-mediated monoclonal antibody treatment - CA-125 (MUC-16) – Immune responses documented, but (to date) negative phase 3 trials (CA-125; folate receptor) – other studies in progress
  11. 11. Clinical Experience (to date) • Stimulation of immune system – Interferon (IV and IP) – Interleukin 2 (IV and IP) – Limited evidence of clinical benefit • CTLA-4 blockade (ipilimumab) – Limited reported experience (combined with GM- CSF – 1 durable response at 4 years) – Several phase 2 trials ongoing (to be reported)
  12. 12. Checkpoint Inhibitors in Ovarian Cancer • Several early phase 2 trials involving multiple agents (mostly abstracts; limited peer-reviewed publications) • Summary of results (to date): – Side effect profile similar to what observed in other indications – Objective response rate (previously treated platinum- resistant disease): 10-20% – Few long-term responses (> 2 years) noted – No objectively validated biomarker in ovarian cancer
  13. 13. Future Directions: Immunotherapy of Ovarian Cancer • Vaccine studies will likely continue, but utility (based on existing experience) is questionable • Immune stimulation - Unknown benefits • Immune checkpoint blockade – Single agent (so far, data not overwhelming based on response rate, but duration of responses will be critical to observe) – Clinically Valid Biomarker (? Number of mutations or presence of particular cancer-associated antigens) – Combination therapy (trials in progress) - major concern with immunologically-based side effects (e.g., myocarditis)
  14. 14. Future Directions?? Checkpoint Inhibitors in Ovarian Cancer • Randomized trials involving hundreds of patients initiated or planned compared to current “standard-of- care” options …….. Why? – In the absence of a validated biomarker does the observed 10-20% response rate with several agents (similar to multiple single anti-neoplastics in ovarian cancer) justify the time to complete, overall effort, and research costs? – Should patients be required to simply wait for the results? – And considering costs/toxicity of such therapy, and increasing number of therapeutic options there is a need to demonstrate ”value” – “getting the right drug(s) to the right patient at the right time” to improve clinical outcomes, based on far more than just tumor type