Masters of Immunology
Pramod K. Srivastava
Cancer Immunol Res September 1 2015 3 (9) 969-977; DOI:10.1158/2326-6066.CIR-15-0134
The FDA-approved dosage of anti–CTLA-4, with and without GM-CSF, was tested on patients with melanoma. Although the antitumor action was equivalent in all groups, the toxic side effects were reduced when GM-CSF was present.
Neoepitopes produced by tumor cells may be key to personalized cancer therapies. Potential MHC-binding peptides were predicted from differential exome sequencing and immunogenic neoepitopes rapidly identified through mixed lymphocyte–tumor cultures, a technique readily applicable to different tumor types.
TIM-3 interferes with tumor immunosurveillance. Expression of TIM-3 in patients, on both tumor and immune cells, was found to correlate with poorer outcomes. Mouse and in vitro studies showed that TIM-3 increases tumorigenic properties and treatment resistance.
Retrospective analysis of blood from cancer patients receiving the combination of anti–CTLA-4 plus GM-CSF revealed no relation between survival and changes in immune cell subsets with treatment. However, short-term survivors had high preexisting PD-1+ CD4 T-cell counts.
Therapeutic PD-1/PD-L1 blockade requires preexisting tumor-infiltrating T cells. In a subset of metastatic RCC patients, antiangiogenic therapy increased T-cell infiltration and PD-L1 upregulation, increasing the likelihood that they may uniquely benefit from combination checkpoint and antiangiogenic therapy.
A mechanistic basis for the synergy between decitabine and anti–CTLA-4 was found. This provides a rationale for initiating trials of combination therapy in ovarian cancer, in which many patients do not benefit from immune checkpoint blockade alone.
Intratumor macrophages were found to be functionally malleable and can support, or be inhospitable to, tumors. Vaccine-induced cytokine-producing CD8 T cells modified intratumoral macrophage subsets, and both T cells and macrophages were indispensable for tumor regressions.
A human antibody to PD-L1, engineered to eliminate Fc effector functions, which potently inhibits PD-L1 function, is in phase III clinical trials. Its characterization here provides clinicians and researchers with a basis for understanding and interpreting clinical trial results.
Control-arm patients from three prostate cancer clinical trials of sipuleucel-T (an autologous APC–based therapy) received APC therapy from their cryopreserved cells. Overall survival may have increased, which suggests that APC therapy may be more robust than estimated.
Adoptive transfer of redirected antitumor T cells can have off-target toxicities. Peptide-MHC specificity can be focused on a single TCR chain, allowing the authors to separate antitumor-reactivity from cross-reactivity, while showing that monitoring for toxicities is still necessary.
Melanomas produce Wnt5a, which promotes the ability of local DCs to drive regulatory T-cell expansion and to generate an immunosuppressive tumor microenvironment. Targeting this system could lead to the development of novel immunotherapeutic strategies.
Current treatments for late-stage pancreatic tumors provide small increases in survival with significant toxicity. The authors' combinatorial approach allows bacterial-based anti-immunosuppression therapy to penetrate the fibrotic capsule of aggressive tumors. The resulting tumor regression demonstrates potential for clinical application.