Immune therapy for women with recurrent ovarian cancer Sarah Adams, MD Associate Professor, Division of Gynecologic Oncology University of New Mexico Comprehensive Cancer Center
The problem: overall survival for women with ovarian cancer is poor due to presentation at advanced stages
Symptoms: Ovarian Cancer it whispers Abdominal fullness/bloating Decreased appetite Pelvic/abdominal pain Urinary urgency/frequency
Mortality from ovarian cancer remains high
Immune therapy has revolutionized cancer treatment
A model of an anti-tumor immune response
A model of an anti-tumor immune response APC T cell
A model of an anti-tumor immune response APC T cell T cell
The goal of immune therapy: To enhance the capacity of T cells to kill tumor cells APC T cell APC
The goal of immune therapy: To enhance the capacity of T cells to kill tumor cells APC T cell T cell
Immune therapy has revolutionized cancer treatment Cancer vaccines
Immune therapy has revolutionized cancer treatment T cell therapy
Immune therapy has revolutionized cancer treatment Immune checkpoint blockade: Blocks inhibitory signaling in the tumor environment that impairs anti-tumor immunity
Immune therapy has revolutionized cancer treatment Immune checkpoint blockade: Blocks inhibitory signaling in the tumor environment that impairs anti-tumor immunity Effectively takes the brakes off of tumorspecific T cells
Long-term survival has been achieved with immune checkpoint blockade in patients with melanoma Patients who respond have had long-lasting benefit Larkin J et al. N Engl J Med 2015;373:23-34.
Long-term survival has been achieved with immune checkpoint blockade in patients with melanoma The problem is knowing who is likely to respond - to avoid giving ineffective treatment to patients with cancer Larkin J et al. N Engl J Med 2015;373:23-34.
Our approach: genetic analysis to select candidates for immune therapy of ovarian cancer Presence of T Presence cell infiltration of CD8+ TILs at tumor (%) sites 100 80 60 40 20 0 BRCA dysfunction BRCA WT
Combination regimens are expected to increase the number of patients who can benefit from checkpoint inhibition Combining tumor-targeted therapy with immune checkpoint blockade (ICB) is expected to increase the proportion of patients who benefit from immune therapy
PARP-inhibitors: Targeted therapy for BRCA- cancers PARP-inhibitors block repair of single-stranded breaks (SSB) in DNA BRCA proteins fix double stranded breaks PARP-inhibitors cause cell death specifically in BRCA- tumor cells
Targeted therapy with PARP-inhibition has improved progression-free but not overall survival in BRCA- ovarian cancer Progression-free survival Overall survival PARP-inhibitor Control
Treatment with a PARP-inhibitor reduces tumor burden but does not improve survival in a BRCA1- ovarian cancer model P<0.0001 PARPi + CLTA4 ab Untreated control PARPi CLTA4 ab Higuchi et al, 2015
Immune checkpoint inhibition had limited efficacy as monotherapy Higuchi et al, 2015
Targeted therapy with a PARP-inhibitor synergized with immune checkpoint blockade in a BRCA1- ovarian cancer model Durable survival was achieved in a majority of tumor-bearing mice P<0.0001 PARPi + CLTA4 ab Untreated control PARPi CLTA4 ab Higuchi et al, 2015
The benefit of combined treatment persisted long after completion of therapy P<0.0001 PARPi + CLTA4 ab Untreated control PARPi CLTA4 ab Treatment from Day 3-Day 25 Higuchi et al, 2015
Results of preclinical studies: Combined therapy with a PARP-inhibitor and an immune checkpoint antibody to CTLA-4 resulted in tumor clearance and durable survival Therapeutic benefit persisted long after completion of therapy This regimen successfully induced protective immune memory Similar results in human BRCA1- cancer cells supported the launch of a clinical trial
UNM INST 1419: Phase I/II trial of Olaparib and Tremelimumab for women with recurrent BRCA mutation associated ovarian cancer Olaparib (PARP-inhibitor) 300mg by mouth twice daily Tremelimumab (immune checkpoint inhibitor): 10mg/kg IV monthly x 6 months, then quarterly Endpoints: Toxicity Response by immune criteria Progression-free survival Overall survival Translational aims: Biomarkers of response Genomic predictors of response Status: Phase I completed. Phase II opened in May 2016. Enrollment ongoing.
Summary Immune therapy represents a powerful treatment strategy for multiple tumor types, including ovarian cancer Genetic profiling may identify patients who are likely to benefit Ovarian cancer associated with BRCA gene mutations may be particularly susceptible to immune therapy Combining immune therapy with tumor-targeted regimens can significantly enhance response Successful treatment can induce protective immune memory
Future directions Broadening inclusion criteria to treat a larger proportion of women with ovarian cancer
Future directions Broadening inclusion criteria to treat a larger proportion of women with ovarian cancer
Future directions Broadening inclusion criteria to treat a larger proportion of women with ovarian cancer Expansion to other tumor types associated with BRCA mutations (breast cancer, prostate cancer, GI cancers)
Future directions Broadening inclusion criteria to treat a larger proportion of women with ovarian cancer Expansion to other tumor types associated with BRCA mutations (breast cancer, prostate cancer, GI cancers) Potential to prevent or overcome acquired treatment resistance through lasting changes in the tumor environment
Acknowledgements Adams Lab *Dallas Flies, PhD *Tomoe Higuchi, MD, PhD Nicole Marjon, MD, PhD Vibha Jha, PhD Gina Mantia-Smaldone, MD Lukas Ronner Jaryse Harris Phyllis Gimotty, PhD, UPenn Funding support: Ovarian Cancer Research Fund * American Cancer Society Oxnard Foundation * Phi Beta Psi Foundation Sandy Rollman Foundation Gynecologic Cancer Foundation Kaleidoscope of Hope Foundation National Institutes of Health American Society of Clinical Oncology Clinical trial funding from AstraZeneca**
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