Combining cancer immunotherapies may open the door to increased number of patients benefitting from treatment. This is what expert, meeting at the 29th annual meeting of the Society for Immunotherapy of Cancer (SITC), which is being held November 6-9, 2014 at the Gaylord National Hotel & Convention Center in National Harbor, MD, expect.

“One of the most promising areas of clinical investigation has been in the arena of combining various types of immunotherapy. Early data suggests that this strategy may lead to additive or even synergistic therapeutic activity. While further studies are needed to better understand the benefit and potential toxicity of specific combinations, the use of combination therapy may provide significant benefit to a much larger number of cancer patients,” noted SITC Vice President Howard Kaufman, MD, Vice President of the Society for Immunotherapy of Cancer, a non-profit medical society dedicated to improving cancer patient outcomes by advancing the development, science and application of cancer immunotherapy.

Reversing T-cell dysfunction
As part of a workshop on on combination immunotherapy (Where Do We Go From Here?), Hassane Zarour, MD, discusses targeting multiple inhibitory receptors to reverse T-cell dysfunction caused by melanoma.

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Research has shown that several dysfunctional tumor antigen-specific CD8+ and CD4+ T cell subsets found at periphery and tumor sites upregulate PD-1, BTLA and Tim-3 expression. PD-1, BTLA and Tim-3 help diminish tumor antigen-specific CD8+ and CD4+ T cell responses in advanced melanoma patients. Further, using monoclonal antibodies to target inhibitory receptors improves the expansion and functions of TA-specific CD8+ and CD4+ T cells. These findings support targeting PD-1, BTLA and Tim-3 as a way to reverse T cell dysfunction caused by melanoma and increase the chance that patients with advanced melanoma will see clinical benefits with their treatment.

F. Steven Hodi, MD, Dana-Farber Cancer Institute, Boston, MA
F. Steven Hodi, MD, Dana-Farber Cancer Institute, Boston, MA

Cytokine and anti-angiogenesis checkpoint combinations
Representing another novel strategy, F. Stephen Hodi, MD, from the Dana-Farber Cancer Institute, Boston, MA, presents on cytokine and anti-angiogenesis checkpoint combinations. Combining ipilimumab (Yervoy®; Bristol-Myers Squibb Company) with blocking vascular endothelial growth factor (VEGF) has shown improved lymphocyte trafficking across the thin layer of cells that line blood and lymph vessels, changes in circulating immune memory, and induction of antibodies to a number of immunogenic targets. This combination is currently being studied in a randomized Phase II study. Another strategy, combining PD-1/PD-L1 antibodies and blocking VEGF is also being investigated.

Cytokine Interaction
The role of cytokine interactions with these novel agents also continues to progress. While not improving progression-free survival, a randomized Phase II study found that adding GM-CSF to ipilimumab improved overall survival as well as lowered the occurrence of high-grade adverse events.

To guide the development and clinical application of combination immunotherapy, attempts to immune-profile the tumor microenvironment are being investigated. Immune-profiling before treatment could lead to the identification of biomarkers that might predict what the response will be, while immune-profiling patients currently in treatment could lead to the identification of biomarkers that may indicate a favorable clinical response. Thus, immune-profiling could lead to early intervention and changing treatment routines in patients who may not be responding.

Preclinical and clinical experience in acute leukemia with bispecific T cell engager
Marion Subklewe from the Department of Internal Medicine III, Klinikum der Universität München, presents experiences with BiTE® antibodies, novel recombinant single chain Ig domain constructs leveraging the endogenous cytotoxic potential of polyclonal T-cells to target malignant cells by utilizing the specific binding properties of variable domains from two different antibodies. BiTE® antibodies, under development for the treatment of leukemia, have demonstrating efficacy in hematologic malignancies. Based on the clinical experience with Blinatumomab (AMG103; Amgen), most advanced BiTE® antibody, in ALL and ex-vivo activity of AMG 330 (another BiTE® antibody targeting CD33) in primary AML samples, Subklewe and colleagues concluded that further development of BiTE® antibodies for targeted T cell-mediated immunotherapy of patients with malignancies. [1]

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