BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial

Accumulating evidence indicates that the innate and adaptive immune systems make a crucial contribution to the antitumour effects of conventional chemotherapy-based and radiotherapy-based cancer treatments. Moreover, the molecular and cellular bases of the immunogenicity of cell death that is induced by cytotoxic agents are being progressively unravelled, challenging the guidelines that currently govern the development of anticancer drugs. Here, we review the immunological aspects of conventional cancer treatments and propose that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies.

Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8 + T cells. We hypothesized that tumor-infiltrating CD8 + T cells harbor latent anti-tumor activity that can be reactivated using combination immunotherapy. Preserved human PDA specimens were analyzed using multiplex immunohistochemistry (IHC) and T cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry and live fluorescent microscopy to assess tumor kill, in addition to T cell expansion and mobilization. Multiplex IHC demonstrated fewer CD8 + T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8 + T cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis. Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA.

A major barrier to effective cancer immunotherapy is immune suppression in favor of tumor progression. Additionally, the accumulation of myeloid-derived suppressor cells (MDSCs) has recently been recognized as a major mechanism of the promotion of immune suppression. However, how MDSCs are induced and the cells from which they arise remains unknown. Although studies have demonstrated that tumor-derived cytokines promote MDSC accumulation and activation, little is known regarding the role of the tumor stroma in MDSC accumulation and activation. In this study, we identified a novel mechanism of MDSC differentiation. Tumor-associated fibroblasts (TAFs) attracted monocytes by the stromal cell-derived factor (SDF)-1a/CXCR4 pathway and induced their differentiation into MDSCs through interleukin (IL)-6-mediated STAT3 activation. TAF-treated monocytes (T-MDSCs) then impaired T-cell proliferation and altered the phenotype and/or function of T-cells in an STAT3-dependent manner. CD11b+ myeloid cells, which resembled T-MDSCs both phenotypically and functionally, were primarily in the peritumoral stroma and a positive association with TAFs in vivo. Additionally, a negative association between CD11b+ myeloid cell densities and overall survival was observed. An increased number of stromal CD11b+ myeloid cells was correlated with Hepatocellular Carcinoma (HCC) progression. Together, our results are the first to show that TAF-derived cytokines, such as IL-6 and SDF-1a, can induce MDSC generation and activation and then impair human anti-tumor immune responses, which create favorable conditions for HCC progression. These data also suggest an important role for STAT3 activation in TAF-mediated MDSC generation and MDSC-mediated immune suppression. Consequently, methods in which immunotherapy is combined with IL-6, SDF-1a or STAT3 inhibition may offer an improved option to eliminate suppressive CD11b+ myeloid cells in HCC patients.