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.

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