Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure)

The invention provides compositions and methods for treating cancers. The method comprises administering a PD-1 axis binding antagonist and an OX40 binding agonist.

Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists

Anti-ox40 antibodies and methods of use

Immune checkpoint inhibitors are becoming standard treatments in several cancer types, profoundly changing the prognosis of a fraction of patients. Currently, many efforts are being made to predict responders and to understand how to overcome resistance in non-responders. Given the crucial role of myeloid cells as modulators of T effector cell function in tumors, it is essential to understand their impact on the clinical outcome of immune checkpoint blockade and on the mechanisms of immune evasion. In this review we focus on the existing clinical evidence of the relation between the presence of myeloid cell subsets and the response to anti-PD(L)1 and anti-CTLA-4 treatment. We highlight how circulating and tumor-infiltrating myeloid populations can be used as predictive biomarkers for immune checkpoint inhibitors in different human cancers, both at baseline and on treatment. Moreover, we propose to follow the dynamics of myeloid cells during immunotherapy as pharmacodynamic biomarkers. Finally, we provide an overview of the current strategies tested in the clinic that use myeloid cell targeting together with immune checkpoint blockade with the aim of uncovering the most promising approaches for effective combinations.

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Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade.

The prognosis and responsiveness to chemotherapy and checkpoint inhibitors differs substantially among patients with bladder cancer (BC). There is an unmet need for biomarkers that can accurately predict prognosis and treatment outcome. Here, we describe the available literature on the prognostic and predictive value of tumor-infiltrating immune cells in BC. Current evidence indicates that a high density of tumor-infiltrating CD8+ T cells is a favorable prognostic factor, whereas PD-L1 expression and tumor-associated macrophages are unfavorable prognostic features. While PD-L1 expression appears unsuccessful as a biomarker for the response to checkpoint inhibitors, there are some indications that high CD8+ T cell infiltration, low transforming growth factor-beta signaling and low densities of myeloid-derived suppressor cells are associated with response. Future studies should focus on combinations of biomarkers to accurately predict survival and response to treatment.

https://www.mdpi.com/2072-6694/12/9/2692/pdf

Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder

Treatment options for metastatic urothelial bladder cancer (UBC) are limited. Mutational complexity is known to be high in UBC and may correlate with increased immunogenicity. MPDL3280A, a human PD-L1 monoclonal antibody containing an engineered Fc-domain designed to promote a Th1-driven response, has demonstrated a RECIST response rate of 43% in diagnostically selected, pretreated patients with UBC. A total of 68 patients (67 with efficacy evaluable) were enrolled in the UBC cohort of the Phase I study; 45% were PD-L1 IHC diagnostic positive as defined by expression of PD-L1 on ≥ 5% of tumor-infiltrating immune cells. In the prescreened UBC population, the prevalence of PD-L1-positive patients was 27%.

Comprehensive gene expression analyses of UBC tumors were conducted to interrogate the tumor immune microenvironment in PD-L1-positive tumors and to identify potential mechanisms associated with response or resistance to MPDL3280A. In this study, PD-L1-positive tumors exhibited a high prevalence of gene expression markers associated with T-effector cells (Teff), including perforin, IFNγ, CD8A, granzyme B, granzyme A and EOMES. Additionally, a low baseline signature of genes associated with myeloid cell markers, including IL1B and IL8, appeared to be statistically significantly associated (P<0.01) with MPDL3280A response, suggesting a potential role for myeloid biology in resistance to MPDL3280A treatment in UBC.

Tumor burden markers, including CA-125, CA19-9 and human chorionic gonadotropin (HCG), have been associated with chemotherapy response markers in UBC. A marked decrease in these markers, including CEA, CA19-9, CA-125 and HCG, was observed with MPDL3280A response after 1 treatment cycle, potentially enabling an on-treatment monitoring alternative for response to therapy. Similarly, evaluation of cytokines on treatment identified markers, including IL-6 and IL-10, elevated as early as Cycle 2 only in patients without response to MPDL3280A. These circulating cytokines and tumor-associated gene signatures suggest potential mechanisms associated with resistance and response to MPDL3280A in UBC and provide a rationale for informed combination strategies to further improve treatment benefit in this indication.

https://jitc.bmj.com/content/jitc/2/Suppl_3/P131.full.pdf

Myeloid cell biology and inhibition of anti-tumor immune responses by MPDL3280A in urothelial bladder cancer

PD-L1 expressed in the tumor microenvironment regulates Th1 immune responses and mediates cancer immune evasion through interactions with PD-1 or B7.1 receptors on activated T cells. MPDL3280A, an engineered human monoclonal antibody, targets PD-L1 and inhibits its function. To identify immunologic predictive and pharmacodynamic biomarkers of MPDL3280A treatment, we performed a comprehensive analysis of tumors and blood samples collected at baseline and/or on treatment from ≈280 patients with locally advanced or metastatic solid tumors, including NSCLC, RCC, melanoma and bladder cancer. Regardless of tumor type, clinical responses were characterized by PD-L1 expression, the presence of markers of T cell activation (Th1 gene signature and CTLA4), and the absence of fractalkine at baseline in the tumor microenvironment. Elevated baseline expression of IFN-γ and IFN-γ-inducible genes (e.g., IDO1 and CXCL9) was associated with MPDL3280A response in melanoma but not NSCLC or RCC. On treatment, responding tumors showed increased infiltration of Th1-dominant immune infiltrate and evidence of adaptive PD-L1 up-regulation. In contrast, progressing tumors displayed the following patterns of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression: (1) few/no TILs and absent PD-L1 expression (immunologic ignorance), (2) TILs present with minimal/no PD-L1 expression (non-functional immune responses), or (3) TILs residing solely around the tumor cell mass outer edge (excluded infiltrate), suggesting that resistance to MPDL3280A may be associated with impaired T cell trafficking and/or function.

Profiling of ≈180 circulating biomarkers revealed that plasma concentrations of IL-18 and interferon-inducible T cell alpha chemoattractant (ITAC) increased in all patients following MPDL3280A treatment, representing a pharmacodynamic measurement of PD-L1 inhibition. In addition, analysis of PBMC showed an increase in T cell activation, as measured by IFN-γ and granzymes A and B gene expression in responders following MPDL3280A treatment, consistent with the observations in responding tumors. Baseline soluble PD-L1 was not associated with response. Some indication-specific biomarkers, such as plasma VEGF, decreased in responders with RCC but not with other indications. In NSCLC, a decrease in tumor burden markers, CA-125 and CEA, was associated with response. Similarly, IL-6 and IL-8 were differentially expressed on treatment in responders vs non-responders. Additionally, responders exhibited a decrease in circulating tumor DNA (ctDNA) in plasma, suggesting that ctDNA may be used to monitor MPDL3280A clinical activity in NSCLC.

In conclusion, these data provide general and indication-specific mechanistic insights into immune checkpoint inhibition, potential mechanisms of response and resistance, as well as identification of potential predictive and pharmacodynamic biomarkers of anti-PD-L1/PD-1 clinical activity across multiple tumor types.

https://jitc.bmj.com/content/jitc/2/Suppl_3/P136.full.pdf

Qun J Wu

Papers

Myeloid cell biology and inhibition of anti-tumor immune responses by MPDL3280A in urothelial bladder cancer

Circulating and tumor-based biomarkers predict clinical activity in cancer patients treated with the engineered anti-PD-L1 antibody MPDL3280A

Myeloid cell biology and inhibition of anti-tumor immune responses by MPDL3280A in urothelial bladder cancer (UBC)