Total Body Irradiation Did Not Improve Response of Adoptive Cell Transfer

Excerpt:

“Adding total body irradiation to preparative lymphodepletion chemotherapy prior to the adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) had no effect on tumor regression in patients with metastatic melanoma, according to the results of a study published in the Journal of Clinical Oncology.

“However, adoptive cell transfer of TILs did mediate the objective complete response of 24% of patients.

“ ‘The nonmyeloablative chemotherapy regimen thus seemed to provide sufficient lymphodepletion for successful adoptive transfer without the need to add total body irradiation,’ wrote researchers led by Stephanie L. Goff, MD, of the National Cancer Institute.”

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TILs Advancing as Melanoma Immunotherapy Option

Excerpt:

“After nearly 30 years of research, tumor-infiltrating lymphocyte (TIL) technology is being investigated as a means of producing personalized immunotherapy for patients with metastatic melanoma in a small clinical trial that may help open the door for broader application in other solid tumor types.

“The form of adoptive cell therapy, which utilizes TILs from the patient’s tumor, represents an intriguing way of overcoming the immunosuppressive power of cancer, according to Jeffrey S. Weber, MD, PhD. The melanoma expert provided an overview of the technology and its potential benefit in a lecture for oncologists and oncology professionals presented by Targeted Oncology, a division of MJH Associates, the publisher of OncologyLive, on February 19 in Miami Beach, Florida. Weber is the deputy director of the Laura and Isaac Perlmutter Cancer Center, co-director of its melanoma program, and head of Experimental Therapeutics at NYU Langone Medical Center.”

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Immune System-Activating Drugs in Combination Treatments May Be Next Big Thing for Melanoma


Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack.  How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs. Continue reading…


Melanoma: A 2013 ‘Progress Report’


The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…


CD137 Accurately Identifies and Enriches for Naturally-Occurring Tumor-Reactive T Cells in Tumor

“Purpose: Up-regulation of CD137 (4-1BB) on recently activated CD8+ T-cells has been used to identify rare viral or tumor antigen-specific T-cells from peripheral blood. Here, we evaluated the immunobiology of CD137 in human cancer and the utility of a CD137-positive separation methodology for the identification and enrichment of fresh tumor-reactive tumor-infiltrating lymphocytes (TILs) or tumor-associated lymphocytes (TAL) from ascites for use in adoptive immunotherapy. Experimental Design: TILs from resected ovarian cancer or melanoma were measured for surface CD137expression directly or after overnight incubation in the presence of tumor cells and homeostatic cytokines. CD137pos TILs were sorted and evaluated for anti-tumor activity in vitro and in vivo. Results: Fresh ovarian TILs and TALs naturally expressed higher levels of CD137 than circulating T-cells. An HLA-dependent increase in CD137 expression was observed following incubation of fresh enzyme-digested tumor or ascites in IL-7 and IL-15 cytokines, but not IL-2. Enriched CD137pos TILs, but not PD-1pos or PD-1neg CD137neg cells, possessed autologous tumor-reactivity in vitro and in vivo. In melanoma studies, all MART-1-specific CD8+ TILs up-regulated CD137 expression after incubation with HLA-matched, MART-expressing cancer cells and antigen-specific effector function was restricted to the CD137pos subset in vitro. CD137pos TILs also mediated superior anti-tumor effects in vivo, compared to CD137neg TILs. Conclusions: Our findings reveal a role for the TNFR-family member CD137 in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of TILs, thus rationalizing its agonistic engagement in vivo and its use in TIL selection for adoptive immunotherapy trials.”


The Promising Landscape of New Treatments for Metastatic Melanoma


In the last few years, patients with the grim diagnosis of metastatic melanoma have gained reasons to feel more hopeful about their chances of beating the disease. Melanoma has become a poster child for new cancer treatment options, with several targeted and immune therapies approved by the U.S. Food and Drug Administration (FDA) and many more in clinical development. Continue reading…


Adoptive T-cell Transfer Therapy and Oncogene-Targeted Therapy for Melanoma: The Search for Synergy

“The clinical strengths of immunotherapy and small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway appear to be largely complementary for the treatment of advanced melanoma. In current practice, most patients with BRAF V600 mutant melanomas will see both modalities. Several in vitro and in vivo studies suggest that combining immunotherapy with MAPK inhibition may have synergistic effects. First, mouse models show that adoptive cell therapy (ACT) can be enhanced by vaccination. Rapid tumor destruction by vemurafenib could provide a vaccine-like stimulus to adoptively transferred T cells. Second, both in mice and in early clinical trials, melanoma metastases treated with MAPK inhibitors seem to display increased T-cell infiltrates. Third, MAPK inhibition upregulates the expression of some melanoma antigens and, therefore, may enhance T-cell recognition of vemurafenib-treated melanomas. Fourth, vemurafenib may sensitize tumor cells to immune destruction. Finally, some investigators have found that an optimal antitumor effect from MAPK inhibition is dependent on an intact host immune response. Currently, the Surgery Branch of the National Cancer Institute has initiated a phase II trial combining the BRAF inhibitor vemurafenib with ACT using tumor-infiltrating lymphocytes in patients with BRAF-mutant tumors to investigate the safety and efficacy of this combination. The proposed mechanisms for synergy between these two modalities can be complex, and their optimal combination may require testing a variety of sequences and schedules.”


Better Performance of CARs Deprived of the PD-1 Brake

“Immunotherapies often permit combinations to increase efficacy. Two approaches are currently leading our field: adoptive therapy with T cells transfected with chimeric antigen receptors and monoclonal antibodies blocking the PD-1/PD-L1 (B7-H1) axis. In this issue of Clinical Cancer Research, preclinical evidence for a synergistic combination of such approaches is reported.”


Better Performance of CARs Deprived of the PD-1 Brake

“Immunotherapies often permit combinations to increase efficacy. Two approaches are currently leading our field: adoptive therapy with T cells transfected with chimeric antigen receptors and monoclonal antibodies blocking the PD-1/PD-L1 (B7-H1) axis. In this issue of Clinical Cancer Research, preclinical evidence for a synergistic combination of such approaches is reported.”