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CICON17 Day 4 Recap: The Tumor Microenvironment and Oncolytic Viruses

September 10, 2017

The final day of the third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference, attended by more than 1,400 scientists from around the world, explored two newer immunotherapy approaches that reflect broader understanding of tumor-immune interactions the field has come to appreciate.

SESSION 10: TARGETING THE HOSTILE TUMOR MICROENVIRONMENT

The tumor microenvironment contains many different types of cells, structures, molecules, and forces—all of which combine to dictate how effective a potential immune response against a tumor is.

The first speaker in this session was The Wistar Institute’s Dmitry Gabrilovich, M.D., Ph.D., who discussed the regulatory role that the myeloid immune cell network plays in the tumor microenvironment. While the inflammation induced by these innate immune cells can be beneficial in the short-term by arousing the immune system to action, chronic inflammation is detrimental due to its ability to foster a hostile tumor microenvironment that supports tumor growth and suppresses anti-tumor immune responses.

Gabrilovich showed that while inhibition of CSF-1R, a pathway intimately involved in the activity of myeloid immune cell populations, led to a decrease in tumor-associated macrophages (TAMs), it increased the amount of tumor-associated neutrophils, a highly immunosuppressive myeloid cell population. This CSF-1R inhibition-associated increase in tumor-associated neutrophils appeared to be due to early accumulation in tumors, rather than through boosting their expansion.

At the same time, expression of chemokines (signaling molecules that control immune cell migration) within tumors increased, especially the expression of the CXCL1 chemokine by cancer-associated fibroblasts (CAFs). This demonstrates the importance of CAFs in neutrophil recruitment, which appears to be negatively regulated by the activity of CSF-1 (which binds CSF-1R). Furthermore, the level of CSF-1 in cancer patients was shown to be inversely associated with neutrophil infiltration into tumors, but showed no association with neutrophils in the peripheral blood. The combination of inhibitors against both CSF-1R and CXCR2 (which is bound by CXCL8) was shown to slow tumor growth in mice, and the addition of an anti-PD-1 checkpoint immunotherapy to this combination drastically enhanced the anti-tumor effects.

Serge Fuchs, M.D., Ph.D., of the University of Pennsylvania, spoke next about the role of type I interferon (IFNa, IFNb, etc.) signaling in the tumor microenvironment. In colorectal cancer specifically, downregulation of the IFNa-receptor-1 (IFNaR1) was found to be associated with worse survival, while mice engineered to express active IFNaR1 had decreased colorectal tumor growth. Further experiments in mice suggested that colorectal tumor growth requires IFNaR1 downregulation, which was associated with reduced adaptive immunity and fewer numbers of CD8+ killer T cells, which were less active and also expressed lower levels of IFNaR1.

Furthermore, Fuchs demonstrated in mice that IFNaR1 downregulation decreased the effectiveness of adoptively transferred normal T cells and CAR T cells, while stabilized IFNaR1 levels were associated with more effective anti-tumor immune responses in mice treated with CAR T cells as well as anti-PD-1 checkpoint immunotherapy. Lastly, Fuchs revealed that inhibition of activity of p38, a signaling pathway that plays a role in cell growth and death and which has been implicated in cancer development, was able to increase T cell infiltration into tumors as well as increase the effectiveness of CAR T cells, an effect which depended on functional IFNaR1 signaling.

Next spoke the University of Iowa’s Yousef Zakharia, M.D., who highlighted the benefits of treating advanced melanoma patients with a checkpoint immunotherapy combination that targeted both the IDO pathway—which exerts immunosuppressive activity in the tumor environment—along with the PD-1 pathway. In one clinical trial, 61% of patients responded to the combination, with 20% of them experiencing a complete response. In addition to the 61% of patients who responded, another 19% saw their disease stabilize.

Alex Y. Huang, M.D., Ph.D., of the Case Western Reserve University School of Medicine, followed Zakharia and spoke about targeting macrophages in a form of bone cancer called osteosarcoma, which commonly metastasizes to the lungs. Specifically, his strategy involved inhibition of the VCAM1-VLA4 signaling axis, which plays a role in cell migration. In one clinical trial, Huang found that 41/49 osteosarcoma patients overexpressed VCAM-1. Using a mouse model that recapitulated VCAM-1 overexpression and lung metastases, he showed that diminishing VCAM-1 subsequently led to a reduction in lung metastases. Metastasis also decreased after depletion of macrophages, whose activity depended on VCAM-1-VLA4 signaling, as demonstrated by the metastasis-reducing ability of both anti-VCAM-1 and anti-VLA4 antibodies.

The last speaker in the tumor microenvironment session was Roberta Melchionna, Ph.D., of the Regina Elena National Cancer Institute, who discussed an important factor in the crosstalk between CAFs and cancer cells in pancreatic and lung cancers. The factor Melchionna investigated—hMENA—is a regulator of the intracellular actin network that governs cellular adhesion and motility. She found that one of its specific forms--hMENADv6—is overexpressed in both tumor cells and CAFs in lung and pancreatic cancer, and is associated with poor prognosis. After CAF activation, which depends on hMENADv6 overexpression, they then secrete GAS6, which promotes cancer cell invasion and maintains the GAS6-AXL axis, which has been found to play a role in the development of cancer and resistance to chemotherapy, radiotherapy, and targeted therapy.

SESSION 11: ONCOLYTIC VIRUSES

John C. Bell, Ph.D., of the Ottawa Hospital Research Institute, led off the session with a discussion of the mechanisms that enable oncolytic viruses—the first of which was approved in the United States in 2015 for metastatic melanoma—to be effective anti-tumor immunotherapies. Above all, they take advantage of the defects in cancer cell signaling (especially the IFNg pathway) that prevent them from being detected and eliminated once they infect cancer cells. This allows them to replicate within tumor cells until they cause the cells to burst (hence the “lytic” portion of their name), which releases tumor-specific neo-antigens that the immune system can then use to launch an adaptive anti-tumor immune response. The activity also has the potential to transform the tumor microenvironment, by converting “cold,” immunologically inert tumors into “hot,” T cell-inflamed tumors in which checkpoint immunotherapies are better able to promote successful anti-tumor immune responses.

One of the oncolytic virus platforms Bell discussed was the Maraba MG1 virus, which has been effective in several preclinical tumor models, including pancreatic, breast, ovarian, and colorectal cancer, as well as glioma and neuroblastoma. These beneficial results were accompanied by increased CD8+ killer T cell responses against a broad variety of tumor-associated antigens, a phenomenon referred to as antigen spread, and also synergized with anti-PD-1 checkpoint immunotherapy to drive a nearly 100% durable survival rate in a challenging mouse tumor model.

A form of the Maraba MG1 virus (MG1-MAGEA3) that expresses the MAGEA3 tumor antigen is now being evaluated in a clinical trial in patients with MAGEA3-expressing solid tumors. Thus far, Bell’s team has observed evidence of viral replication and a remodeling of the tumor microenvironment that is characterized by an increase in the expression of molecules associated with adaptive immune responses. Another trial evaluating MG1-MAGEA3 in combination with anti-PD-1 checkpoint immunotherapy is also in the works.

Amgen’s Pedro J. Beltran, Ph.D., followed Bell with a look at Talimogene laherparepvec (T-Vec)—the only oncolytic virus immunotherapy approved in the U.S.—which consists of a modified herpes virus that is injected directly into melanoma lesions. Like Bell’s MG1 virus, T-Vec’s clinical efficacy derives from both direct oncolytic activity as well as the stimulation of subsequent immune responses against tumor-associated antigens. T-Vec is also equipped with the gene for GM-CSF, which is designed to promote immune cell expansion. A mouse version of T-Vec has already shown increased effectiveness in combination with anti-PD-1 as well as anti-CTLA-4 checkpoint immunotherapies, an approach that is currently being evaluated in multiple phase III clinical studies.

The next speaker was Stephen J. Russell, M.D., Ph.D., of the Mayo Clinic, whose talk mainly focused on an oncolytic virus platform that utilizes the vesicular stomatitis virus (VSV-IFNb-NIS). While the VSV-IFNb-NIS platform targets innate immune defects and lyses cells similar to the previous oncolytic viruses mentioned, it also delivers the IFNb gene to tumor cells (which can restore immune signaling). It also contains the NIS gene, which can be used for imaging to monitor the spread of the virus to boost its anti-tumor activity through a technique known as radiovirotherapy. In several mouse models of cancer, a single intravenous infusion of VSV-IFNb-NIS was shown to be effective at stimulating immune responses against tumors. In humans, it has led to several responses in several patients after intratumoral injection into liver tumors, both primary ones and colorectal tumors that had metastasized to the liver.

Russell also highlighted another oncolytic virus platform that utilizes the measles virus (MV-NIS) and targets the CD46 molecule, which can protect tumors from the immune system. Rather than causing tumor cells to burst, the MV-NIS platform induces tumor death by fusing with them. In a phase I trial with multiple myeloma patients, MV-NIS induced responses against the virus as well as increased T cell levels in all patients, and demonstrated anti-tumor activity at the top dose level, albeit only in patients who lacked presence of the measles virus in their blood. One of the twelve patients even had a complete response that also eliminated a distant, disseminated cancer. Russell suggested the mechanism was likely an initial de-bulking of the tumor followed by long-term immune control.

Finally, Tala Shekarian, Ph.D., of the Leon Berard Cancer Research Center, ended the final session of CICON17 by highlighting the ability of an oncolytic Rotavirus vaccine to overcome checkpoint immunotherapy resistance by reprogramming the tumor microenvironment. In a mouse model of neuroblastoma, the oncolytic Rotavirus vaccine led to activation of tumor-infiltrating T cells within the first 24 hours after injection and induced tumor cell death while sparing the healthy fibroblasts in the tumor microenvironment. Additionally, when the Rotavirus injection was combined with anti-CTLA-4 checkpoint immunotherapy, it was able to completely eliminate both mouse neuroblastomas and lymphomas in a CD8+ killer T cell-dependent fashion. Furthermore, all of the mice that experienced complete tumor regression were subsequently resistant to tumor re-challenge, indicating the development of successful anti-tumor immune memory that should be the ultimate goal of all immunotherapy strategies.

This concludes our daily coverage of the third CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.


Photos courtesy of the Association for Cancer Immunotherapy (CIMT)/Andrea Enderlein

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