PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance

Verma, Vivek; Shrimali, Rajeev; Ahmad, Shamim; Dai, Winjie; Wang, Hua; Lu, Sumin; Nandre, Rahul; Gaur, Pankaj; López, José Alejandro; Sade-Feldman, Moshe; Yizhak, Keren; Bjorgaard, Stacey L.; Flaherty, Keith T.; Wargo, Jennifer A.; Boland, Genevieve M.; Sullivan, Ryan J.; Getz, Gad; Hammond, Scott A.; Tan, Ming; Qi, Jingjing; Wong, Phillip; Merghoub, Taha; Wolchok, Jedd D.; Hacohen, Nir; Janik, John E.; Mkrtichyan, Mikayel; Gupta, Seema; Khleif, Samir N.

doi:10.1038/s41590-019-0441-y

Cited by 240 publications

(236 citation statements)

References 53 publications

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“…It is being assessed as a target in combination with immunotherapy 23, 24 . In agreement with our data, CD38 expression was recently shown to be upregulated post-immunotherapy and was found to be associated with negative outcomes in a murine checkpoint inhibition model and in human patients 25 . Based on the current knowledge of the function of CD38 and CD39 and our observation that CD4+CD38+CD39+ immunophenotypic clusters are associated with poor patient outcomes, we hypothesize that this population is immunosuppressive.…”

Section: Discussionsupporting

confidence: 92%

Nivolumab and Ipilimumab in Metastatic Melanoma Are Associated with Distinct Immune Landscape Changes and Response-Associated Immunophenotypes

Woods

Laino

Winters

et al. 2020

Preprint

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The reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well-described. We used high-parameter flow cytometry and a novel computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO>IPI or IPI>NIVO. The two treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response. Only two immunophenotypes were shared but had opposing relationships to response/survival. To understand the impact of sequential treatment on response/survival, phenotypes that changed after the initial treatment and differentiated response in the other cohort were identified. Immunophenotypic changes occurring post-NIVO were predominately associated with response to IPI>NIVO, but changes occurring post-IPI were predominately associated with progression with NIVO>IPI. Among these changes, CD4+CD38+CD39+CD127-GARP- T-cell subsets were increased after IPI treatment and were negatively associated with response/survival for the NIVO>IPI cohort.

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Section: Discussionsupporting

confidence: 92%

Nivolumab and Ipilimumab in Metastatic Melanoma Are Associated with Distinct Immune Landscape Changes and Response-Associated Immunophenotypes

Woods

Laino

Winters

et al. 2020

Preprint

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“…CS1 is expressed in more than 90% of patient MM samples and not expressed on nonhematological and essential tissues such as the stomach, lung, kidney, brain, and heart 17,18,25 . A previous study has shown that CS1 is more commonly expressed than BCMA on patient-derived MM samples 32 . As such, CS1 is an ideal target to be paired with the more heterogeneously expressed but clinically validated BCMA for MM treatment.…”

Section: Discussionmentioning

confidence: 96%

“…5). A recent study reported that PD-1 blockade actually induces dysfunction in sub-optimally primed T cells 32 . In our study, anti-PD-1 treatment showed clear beneficial effects at early time points, when tumor burden was still present.…”

Section: Discussionmentioning

confidence: 99%

“…5a). Verma et al recently reported that PD-1 blockade in suboptimally primed T cells can induce a dysfunctional PD-1 + /CD38 + population, resulting in decreased anti-tumor efficacy 32 . In our study, animals were given twice-weekly injections of anti-PD-1 even after they have achieved tumor clearance, thus the CAR-T cells may have become dysfunctional due to continual exposure to anti-PD-1 in the absence of antigen stimulation.…”

Section: Combination Therapy With Anti-pd-1 Antibody Enhances Initialmentioning

confidence: 99%

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Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

Zah

Nam

Bhuvan

et al. 2020

Preprint

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ABSTRACTChimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies but also demonstrated marked vulnerability to antigen escape and tumor relapse. Here, we report the rational design and systematic optimization of bispecific CAR-T cells with robust activity against multiple myeloma (MM), including heterogeneous MM that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit significantly higher CAR expression levels and greater antigen-stimulated proliferation compared to T cells that co-express individual BCMA and CS1 CARs. Compared to single-input BCMA- or CS1-targeting CAR-T cells, BCMA/CS1 bispecific CAR-T cells significantly prolong the survival of animals bearing heterogeneous MM tumors. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, but CAR-T cell treatment alone was able to achieve durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets.

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“…Combination of anti‐CD38 monoclonal antibodies and PD‐1/PD‐L1 blockade to improve disease response was also recently suggested by Verma et al They reported that PD‐1 blockade in subprimed CD8 cells induced dysfunctional PD‐1 + CD38 hi CD8 + cells and anti‐PD1 resistance that may be reverted by the use of anti‐CD38 monoclonal antibodies.…”

Section: Discussionmentioning

confidence: 68%

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

et al. 2020

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Background Daratumumab (Dara), an anti‐CD38 monoclonal antibody, has an immunologic mechanism of action through targeting of CD38 expressing immune cells in patients with multiple myeloma (MM). Furthermore, it was recently shown that CD38 upregulation in tumors, is a major mechanism of acquired resistance to antiprogrammed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1). Therefore, we decided to evaluate the immunomodulatory effects of CD38 blockade by Dara on the PD‐L1 expressing immune cells. Methods We analyzed CD38 and PD‐L1 expression on immune cells at different time points in 18 newly diagnosed MM receiving bortezomib, lenalidomide and dexamethasone, with or without Dara. Results We first confirmed that CD38 is widely expressed on immune cells, with the strongest expression on plasmacytoid dendritic cells (pDC). Furthermore, Dara induces a strong depletion of pDC in addition to the well‐known rapid depletion of natural killer cells. Finally, we found that PD‐L1 expression on antigen‐presenting cells (APC) increases with MM treatment in patients that did not received Dara, while addition of Dara prevents this increase. Conclusion Overall, our results suggest new mechanisms of action of Dara through depletion of pDC and prevention of PD‐L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD‐L1/PD‐1 pathway in patients with MM.

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PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance

Cited by 240 publications

References 53 publications

Nivolumab and Ipilimumab in Metastatic Melanoma Are Associated with Distinct Immune Landscape Changes and Response-Associated Immunophenotypes

Nivolumab and Ipilimumab in Metastatic Melanoma Are Associated with Distinct Immune Landscape Changes and Response-Associated Immunophenotypes

Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

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