Immunotherapy Update for Ovarian Cancer
Download as PPTX, PDF4 likes20,015 views
This document discusses the historical and current perspectives on immunotherapy for ovarian cancer, highlighting the relationship between immune system responses and cancer regression. It reviews different immunotherapeutic approaches, including vaccines, immune stimulation, and checkpoint inhibitors, while also analyzing their clinical efficacy and toxicity profiles. Future directions for research involve evaluating combination therapies, the development of valid biomarkers, and the need for effective clinical outcomes amidst high costs and side effects associated with immunotherapy.
Immunotherapy Update for Ovarian Cancer
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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