The notion of commandeering the immune system to treat cancer actually dates back more than a century with intratumoral bacterial injections to try and elicit tumor regression. Since then, immune therapies now run the gamut from bone marrow transplantation, to recombinant cytokine administration, to vaccines, and to therapeutic monoclonal antibodies (mAb) that either block oncogenic pathways or deliver a linked cytotoxic agent to specific tumor cells.

 More recently, however, the ability to therapeutically modulate the endogenous T-cell response to trigger new antitumor responses has reinvigorated the cancer immunotherapy community to seriously explore this new therapeutic approach.

The discovery of tumor-associated antigens (TAAs) and immune responses to these antigens has accelerated development of immunotherapy as an antitumor strategy. The immune response is mediated by activating and deactivating signals. T-cell activation occurs via multiple interactions: (1) TAA epitopes bound to major histocompatibility complex molecules on antigen-presenting cells (APCs), which interact with T-cell receptors (TCR), and (2) CD80/86(B7) costimulatory molecules expressed on APCs that bind to CD28 on T-cells. On the other hand, CTLA-4 is a receptor expressed by activated T cells that, after binding to CD80/86 and displacing CD28, will deactivate the immune response. While each of the events of the immune response represents distinct opportunities for therapeutic intervention, encouraging clinical results in CTLA4- based therapy brought forth a new era for immune-modulatory therapy.

Ipilimumab, a humanized mAb against CTLA-4, is FDA-approved for treating primary or recurrent metastatic melanoma. In the first seminal phase III study of ipilimumab, Hodi et al compared ipilimumab plus gp100 versus ipilimumab alone versus gp100 alone.

 Patients receiving ipilimumab had a significant overall survival (OS) benefit compared with those who did not (10.1 months, 10.0 months, 6.4 months, respectively).

In the second pivotal phase III study, Robert et al evaluated ipilimumab plus dacarbazine versus dacarbazine alone.

 Again, the ipilimumab-containing regimen demonstrated superior OS rates (11.2 months vs 9.1 months). Of particular excitement, however, was the significantly higher proportion of patients in the ipilimumab arm who achieved a durable survival (≥3 years) compared with those in the control arm (20.8% vs 12.2%). While the antitumor effects here capitalize on the T-cell response to TAAs, it’s important to recognize that the same immune-activating events can also occur in the context of virus-infected cells.

Nearly all cervical cancers are attributable to human papillomavirus (HPV). Therefore, immunomodulatory treatment against cervical cancer cells expressing HPV antigens should be especially attractive. While standard treatment for locally advanced cervical cancer (LACC) is radiation with concurrent chemotherapy, patients with lymph node metastases are nevertheless at high risk for relapse. Although data regarding ipilimumab and chemoradiation are limited, preclinical and in vitro studies indicate that radiotherapy may upregulate immune-mediators associated with tumors, thereby affecting the efficacy and durability of radiotherapy. However, treating cervical tumors with chemoradiation likely results in HPV/ tumor-specific T-cell activation by increasing antigen presentation within the tumor and in draining lymph nodes. Hypothetically, using ipilimumab to prolong this T-cell activation may augment the patient’s ability to clear the tumor. This novel treatment strategy would seem particularly relevant for the women at high risk for recurrence despite standard chemoradiation.

With that in mind, the Gynecologic Oncology Group (GOG) activated a nationwide phase I trial to evaluate sequential ipilimumab given after chemoradiation in patients with LACC and nodal disease (GOG9929; NCT01711515). Since ipilimumab with chemoradiation had not been previously evaluated, the primary objective of this phase I study is to estimate the maximum-tolerated dose and dose-limiting toxicities of adjuvant ipilimumab in this population. Furthermore, this study will also determine the feasibility and toxicity profile of this treatment regimen, as well as clinical endpoints, such as progression-free survival, recurrence rates and patterns of recurrence.

While the biological rationale for this treatment strategy is sound, the specific kinetics of the immune response while undergoing immune-modulatory therapy are unknown. Similarly, predictors of patients more likely to respond to CTLA-4 blockade are also unknown. Recognizing the importance of these questions, the GOG9929 study chair, Yvonne Lin, MD, University of Southern California (USC), in conjunction with her colleagues, internationally-renowned immunologists, W. Martin Kast, PhD, and Diane DaSilva, PhD, devised a set of correlative studies as part of GOG9929 to longitudinally interrogate the immune response of patients on-study. These correlative studies are being performed at the USC Norris Comprehensive Cancer Center Immune-Monitoring Core and will delineate the role and kinetics of the immune system and T-cell regulation, as well as examine the differential expression of immune markers on lymphocytes as possible markers of immune responsiveness.

This trial is the first of its kind for the primary treatment of cervical cancer and represents a shift in our treatment paradigm for LACC. As we collect information from GOG9929, we also expect to expand our knowledge of the immune response. Furthermore, additional therapeutic approaches to modulate T-cell function by targeting other regulatory axes, most notably PD-1/PD-L1(-L2) are also on the horizon. Encouraging clinical data therapeutically blocking this axis have been reported, and will certainly fuel additional studies in cervical cancer.

		Figure. Schema representing rationale for immune system activation during chemoradiation treatment for cervical cancer

		Ag indicates antigen; APC, antigen-presenting cell; ChemoRT, chemoradiation; MHC, major histocompatibility complex; TAA, tumor-associated antigens.

			Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. 

			Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. 

			Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. 

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The notion of commandeering the immune system to treat cancer actually dates back more than a century with intratumoral bacterial injections to try and elicit tumor regression. 

Yvonne Lin, MD, MS

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Immunotherapy Examined as Treatment Option in Locally Advanced Cervical Cancer