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.”


Antagonist Antibodies to PD-1 and B7-H1 (PD-L1) in the Treatment of Advanced Human Cancer—Letter


Antagonist Antibodies to PD-1 and B7-H1 (PD-L1) in the Treatment of Advanced Human Cancer—Letter


Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells

“Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8+ T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell–inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3+ regulatory T cells (Tregs), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8+ T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of Tregs, in the tumor microenvironment depended on the presence of CD8+ T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell–inflamed tumor microenvironment.”


Advances in Immunotherapy Brighten Prospects for People with Cancer

The enthusiasm for anticancer immunotherapies continues to build, with two treatments already approved by the U.S. Food and Drug Administration (FDA) and clinical trials underway for a variety of promising new candidates. The latest approaches include targeting a protein called PD-L1, which shields tumor cells from immune system attacks. In a phase I clinical trial of a PD-L1 blocker made by MedImmune, early results suggest that this treatment shrinks melanomas as well as kidney, lung, and colon tumors. Next, the researchers hope to open this trial to people with head and neck cancers as well. Another approach entails adding the gene for an immune system booster (interferon beta) to a therapeutic virus (vesicular stomatitis virus) that kills cancer cells, but not normal ones. This treatment is being tested on liver cancer in a phase I trial and early results are encouraging.


Advances in Immunotherapy Brighten Prospects for People with Cancer

The enthusiasm for anticancer immunotherapies continues to build, with two treatments already approved by the U.S. Food and Drug Administration (FDA) and clinical trials underway for a variety of promising new candidates. The latest approaches include targeting a protein called PD-L1, which shields tumor cells from immune system attacks. In a phase I clinical trial of a PD-L1 blocker made by MedImmune, early results suggest that this treatment shrinks melanomas as well as kidney, lung, and colon tumors. Next, the researchers hope to open this trial to people with head and neck cancers as well. Another approach entails adding the gene for an immune system booster (interferon beta) to a therapeutic virus (vesicular stomatitis virus) that kills cancer cells, but not normal ones. This treatment is being tested on liver cancer in a phase I trial and early results are encouraging.


New Drug May Mobilize the Immune System to Attack Tumors

A new drug called MPDL3280A appears to shrink tumors in patients with a range of different cancers, including lung cancer and melanoma. In an ongoing clinical trial, MPDL3280A shrank tumors in 21% of patients with advanced cancer. Response rates were even higher in subsets of patients with lung cancer (22%) or melanoma (29%). Treatment benefits lasted from 3 to 15 months and counting; 26 of the 29 patients who benefited continue to respond to this day. There was wide variation in how quickly patients responded to treatment, with some experiencing significant improvement within days, and others after weeks of unresponsiveness. MPDL3280A was generally well tolerated, with few cases of severe side effects.


Antibody Against PD-L1 May Mobilize the Immune System to Attack Tumors

A new drug called MPDL3280A appears to shrink tumors in patients with a range of different cancers, including lung cancer and melanoma. In an ongoing clinical trial, MPDL3280A shrank tumors in 21% of patients with advanced cancer. Response rates were even higher in subsets of patients with lung cancer (22%) or melanoma (29%). Treatment benefits lasted from 3 to 15 months and counting; 26 of the 29 patients who benefited continue to respond to this day. There was wide variation in how quickly patients responded to treatment, with some experiencing significant improvement within days, and others after weeks of unresponsiveness. MPDL3280A was generally well tolerated, with few cases of severe side effects.