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