Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

Herbst, Roy S.; Soria, Jean Charles; Kowanetz, Marcin; Fine, Gregg; Hamid, Omid; Gordon, Michael; Sosman, Jeffery A.; McDermott, David F.; Powderly, John D.; Gettinger, Scott; Kohrt, Holbrook E.; Horn, Leora; Lawrence, Donald P.; Rost, Sandra; Leabman, Maya; Xiao, Yuanyuan; Mokatrin, Ahmad; Koeppen, Hartmut; Hegde, Priti S.; Mellman, Ira; Chen, Daniel S.; Hodi, F. Stephen

doi:10.1038/nature14011

Cited by 4,507 publications

(4,231 citation statements)

References 32 publications

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“…As some of these chemokines are reported to be associated with trafficking of T cells into tumours and other anti‐tumour effects these in vitro data demonstrate further mechanisms induced by IMCgp100 that may benefit patients treated with the drug 32. It has also been reported that IFN‐ γ and MIG were significantly higher in melanoma patients who had a response to anti‐programmed death‐ligand 1 (PDL‐1) treatment versus those with progressive disease 33. MIP‐1 is produced in large quantities by cytotoxic T cells and only modestly by CD4 + Tem lymphocytes, in line with its role in inducing tumoricidal activity and promoting the T helper type 1 phenotype 34.…”

Section: Discussionmentioning

confidence: 99%

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

et al. 2017

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SummaryThe success of immune system‐based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC™ molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti‐CD3 scFv antibody) were previously shown to redirect CD8+ and CD4+ T cells against tumours. Here we present evidence that IMCgp100 (ImmTAC recognizing a peptide derived from the melanoma‐specific protein, gp100, presented by HLA‐A*0201) efficiently redirects and activates effector and memory cells from both CD8+ and CD4+ repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD8+ T cells redirected by IMCgp100 are potent killers of melanoma cells. Furthermore, CD4+ effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMCgp100. The majority of T cell subsets belonging to both the CD8+ and CD4+ repertoires secrete key pro‐inflammatory cytokines (tumour necrosis factor‐α, interferon‐γ, interleukin‐6) and chemokines (macrophage inflammatory protein‐1α‐β, interferon‐γ‐inducible protein‐10, monocyte chemoattractant protein‐1). At an individual cell level, IMCgp100‐redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti‐cancer response. This study demonstrates that IMCgp100 induces broad immune responses that extend beyond the induction of CD8+ T cell‐mediated cytotoxicity. These findings are of particular importance because IMCgp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma.

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Section: Discussionmentioning

confidence: 99%

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

et al. 2017

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“…The results from the present study, with immune cell-specific PD-L1 expression being an independent prognostic factor while its expression in tumour cells was not, are coherent with previous research 16 , 23-26 and demonstrate that PD-L1 expression in immune cells and tumour cells might carry different prognostic values and might be regulated by distinct mechanisms. Furthermore, although tumour cell-specific PD-L1 expression has been validated as a predictive marker for response to PD-1 or PD-L1 blockade in several cancers, 11 , 38 , 39 recent studies now suggest that PD-L1 expression in tumour-infiltrating myeloid and T cells also play a critical role in immunosuppression, 38 , 40-43 and should possibly be taken into account in assessment scoring for PD-1/PD-L1 blockade.…”

Section: Discussionmentioning

confidence: 99%

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

et al. 2018

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Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

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“…28 , 29 However, human IgG1 containing avelumab was shown to have a toxicity profile comparable to ADCC-null PD-L1-blocking antibodies 30-32 with low levels of lysis of PBMCs in vitro . 27 , 33 Moreover, NK cell-mediated ADCC by avelumab was shown to enhance its therapeutic functionality.…”

Section: Discussionmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by ‘on-target/off-tumor’ binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment.To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.

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Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

Cited by 4,507 publications

References 32 publications

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

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Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

Cited by 4,507 publications

References 32 publications

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

Contact Info

Product

Resources

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Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells