NATIONAL HARBOR, MD—Decades of research aimed at harnessing immune system approaches to fighting cancer are paying off. So said speakers at the 24th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc), held at the Gaylord National Hotel and Convention Center here.
Although there have been disappointments clinically along the way, the research is yielding fruit in a number of areas showcased at the meeting, including basic immunology, therapeutic cancer vaccines, adoptive cell transfer, viral and cellular proteomic targets, manipulation of the tumor microenvironment, and cancer and inflammation. In informal conversation with OT, several physicians said they believe immunotherapy represents the future of cancer treatment because it promises effective tumor eradication with fewer side effects.
In his talk, keynote speaker Mark M. Davis, PhD, Professor of Microbiology and Immunology and a Howard Hughes Medical Institute investigator at Stanford University School of Medicine, cited an increased understanding of T-cell recognition as one factor helping to usher in what he termed “the coming golden age of human immunology and immunotherapy.”
Dr. Davis noted that since T-cell recognition is a key event in the development of most immune responses, the use of tumor-specific T cells for cancer immunotherapy makes sense scientifically. His research is focused in part on T-cell recognition of specific peptide-MHC complexes (a desired outcome for cancer immunotherapies) and on self-antigen reactive T cells—abundant in peripheral blood—and how the immune system keeps these cells from causing autoimmunity.
“We need to develop a much more extensive knowledge of human immunology, independent of animal models, in order to correctly navigate the challenges of developing immunotherapies,” he emphasized.
Several speakers said they believe that immunotherapy—such as therapeutic cancer vaccines—will be most promising clinically when used in combination with other cancer treatments. “Preclinical data have now demonstrated, and clinical data are emerging, on the benefit of combination therapies employing chemotherapy, hormone therapy, small molecule targeted therapy and local radiation with vaccine,” said Jeffrey Schlom, PhD, Chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute.
“Several of these additional therapies, when used in appropriate dose scheduling regimens, have the ability to enhance host immune function and/or alter the phenotype of tumor cells to render them more susceptible to vaccine-mediated T-cell killing.”
Dr. Schlom also described how therapeutic vaccine efficacy can be enhanced using poxviral vectors expressing transgenes that encode one or more tumor-associated antigens and three T cell costimulatory molecules (B7.1, ICAM-1, LFA-3), designated as TRICOM. A recent 43-center randomized Phase II, vector-controlled study of patients with metastatic, castrate-resistant prostate cancer showed that the PSA-TRICOM therapeutic vaccine (PROSTVAC) increased patient survival in the treatment group vs. the control group.
He noted that a Phase III trial of this promising therapeutic vaccine is expected to begin in 2010, and PROSTVAC is being developed by NCI and private industry under a Cooperative Research and Development Agreement.
Glenn Dranoff, MD, Associate Professor of Medicine at Harvard Medical School and the Dana-Farber Cancer Institute, agreed with Dr. Schlom that immunotherapies might be most effectively used in combination: “Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits,” he said.
His own research is focused on granulocyte-macrophage based therapeutic cancer vaccines. He has discovered several of the molecular pathways underlying a dual targeting of melanoma cells and the tumor vasculature, a finding that has led him to believe that combining therapeutic anti-cancer vaccines with anti-angiogenic treatments might be a good clinical strategy.
Carl H. June, MD, Director of Translational Research and Professor in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania, is using engineered T cells for cancer immunotherapy. “We are exploring the use of engineered T cells bearing chimeric receptors and strategies to augment their anti-tumor efficacy in adoptive transfer settings,” he said.
Specifically, his preclinical research is focused on using lentivral engineered T cells that incorporate a tumor resistance genotype, which, he said, should have an “improved function for cancer immunotherapy.” This preclinical research is being done in humanized mouse models bearing tumor xenografts; the engineered T cells are able to eradicate large, well-established tumors in these preclinical models, he noted.
In using the technique of adoptive cell transfer, the state of differentiation of anti-tumor T cells before their transfer is “critically important for their effectiveness,” said Nicholas P. Restifo, MD, an investigator in NCI's Surgery Branch. Dr. Restifo and his collaborators are focusing on identifying the functional and phenotypic qualities of adoptively transferred T cells that mediate tumor regression in melanoma.
He said that “younger” T cells appear to be more effective, and that these young, undifferentiated T cells must be capable of maturing into fully functional T cells after adoptive transfer.
The realization that these younger T cells have increased effectiveness in adoptive cell transfer for melanoma immunotherapy points the way overall toward the use of the most appropriate cells for immunotherapy in patients with cancer, he said.