Anti-PD-L1/TGFßR2 (M7824) fusion protein induces immunogenic modulation of human urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis.

BACKGROUND: Avelumab has recently been approved by the Food and Drug Administration for the therapy of Merkel cell carcinoma and urothelial carcinoma. M7824 is a novel first-in-class bifunctional fusion protein comprising a monoclonal antibody against programmed death-ligand 1 (PD-L1, avelumab), fused to the extracellular domain of human transforming growth factor beta (TGFß) receptor 2, which functions as a TGFß "trap." Advanced urothelial tumors have been shown to express TGFß, which possesses immunosuppressive properties that promote cancer progression and metastasis. The rationale for a combined molecule is to block the PD-1/PD-L1 interaction between tumor cells and immune cell infiltrate and simultaneously reduce or eliminate TGFß from the tumor microenvironment. In this study, we explored the effect of M7824 on invasive urothelial carcinoma cell lines. METHODS: Human urothelial (transitional cell) carcinoma cell lines HTB-4, HTB-1, and HTB-5 were treated with M7824, M7824mut (M7824 that is mutated in the anti-PD-L1 portion of the molecule and thus does not bind PD-L1), anti-PD-L1 (avelumab), or IgG1 isotype control monoclonal antibody, and were assessed for gene expression, cell-surface phenotype, and sensitivity to lysis by TRAIL, antigen-specific cytotoxic T lymphocytes and natural killer cells. RESULTS: M7824 retains the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti-PD-L1. However, compared to anti-PD-L1, M7824 increases (A) gene expression of molecules involved in T-cell trafficking in the tumor (e.g., CXCL11), (B) TRAIL-mediated tumor cell lysis, and (C) antigen-specific CD8+ T-cell-mediated lysis of tumor cells. CONCLUSIONS: These studies demonstrate the immunomodulatory properties of M7824 on both tumor cell phenotype and immune-mediated lysis. Compared to anti-PD-L1 or M7824mut, M7824 induces immunogenic modulation of urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. These findings show the relevance of the dual blockade of PD-L1 and TGFß in urothelial carcinoma cell lines and thus support the rationale for future clinical studies of M7824 in patients with urothelial cancer.

Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines.

This study investigated the effects on the tumor microenvironment (TME) of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in two murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using three endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the TME, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can, thus, have a dramatic impact on the effectiveness of cancer immunotherapy.

Rehabilitation in neuro-oncology: a meta-analysis of published data and a mono-institutional experience.

BACKGROUND: Rehabilitation for cancer patients with central nervous system (CNS) involvement is rarely considered and data on its use are limited. The purpose of the present study is to collect all available published data on neuro-oncology rehabilitation and perform a meta-analysis where results were presented in a comparable manner. Moreover, the authors report results on cancer patients with neurological disabilities undergoing rehabilitation at their unit. STUDY DESIGN: A PubMed search was performed to identify studies regarding cancer patients with CNS involvement undergoing inpatient physical rehabilitation. Studies with a complete functional evaluation at admission and discharge were selected. As the most common evaluation scales were Functional Independence Measure (FIM) and Barthel Index (BI), only articles with complete FIM and/or BI data were selected for the meta-analysis. Moreover, 23 cancer patients suffering from diverse neurological disabilities underwent standard rehabilitation program between April 2005 and December 2007 at the San Raffaele Pisana Rehabilitation Center. Patient demographics and relevant clinical data were collected. Motricity Index, Trunk Control Test score, and BI were monitored during rehabilitation to assess patient progresses. BI results of patients in this study were included in the meta-analysis. RESULTS: The meta-analysis included results of a total of 994 patients. A statistically significant (P < .05) improvement of both BI and FIM scores was demonstrated after rehabilitation (standardized mean difference = 0.60 and 0.75, respectively). Functional status determined by either FIM or BI improved on average by 36%. CONCLUSION: Published data demonstrate that patients with brain tumors undergoing inpatient rehabilitation appear to make functional gains in line with those seen in similar patients with nonneoplastic conditions.