Periodic Reporting for period 3 - ONCO-VAX (A multifaceted cancer immunotherapy based on an immune checkpoint-modulating chimeric oncolytic virus vector in combination with a dendritic cell vaccine)
Reporting period: 2023-04-01 to 2024-09-30
Breakthroughs in the field of immuno-oncology have offered new hope for the possibility of safe, systemic, and durable tumor responses to an otherwise daunting disease. Promising immunotherapeutic approaches, such as adoptive cell therapy and immune checkpoint blockade, have gained a lot of attention recently as the new face of cancer therapy, but in practice, the reach of these strategies has proven to be extremely limited. Hepatocellular carcinoma (HCC), with a rising incidence and lack of effective therapies, represents a major worldwide health concern. Despite the inflammation associated with HCC, these tumors are characterized by a high degree of immune tolerance, due to a variety of interacting mechanisms, which present a hurdle for effective immunotherapeutic responses. In order for immune-based therapies to be effective for hepatic tumors, it is necessary to modulate the tolerogenic environment in the liver. Oncolytic viruses (OVs) can offer a novel approach to address the challenge of HCC by combining the benefits of direct tumor cell oncolysis with modulatory effects to break immune tolerance.
The central aim of ONCO-VAX is to address the current challenges in the field of immune-oncology through the rational design of a multi-mechanistic combinatorial approach based on the underlying biology of the tumor microenvironment. By first gaining a better understanding of the immune-suppressive microenvironment in HCC and the immune modulatory responses to OV therapy in HCC, we aimed to rationally design a therapeutic regimen using a novel chimeric vector, VSV-NDV, as the basis for a cutting edge and broad-acting oncolytic viral vaccine. In this project, the VSV-NDV technology is used as a viro-immunotherapeutic platform for HCC, with further engineering to express an immune checkpoint-modulating gene to ameliorate the immune-suppression, while simultaneously activating the antitumor immune response via induction of immunogenic cell death through virus-mediated oncolysis. As an additional layer of therapy, a novel anti-cancer vaccine is under development, in which antigen presenting cells, called dendritic cells (DCs), are prepared in a unique manner, whereby they will be activated and loaded with antigens using VSV-NDV-infected tumor oncolysates ex vivo.
This multifaceted approach represents an innovative and crucial step forward revolutionizing immune oncology and providing new hope to cancer patients with immune-suppressive solid tumors.
The central aim of ONCO-VAX is to address the current challenges in the field of immune-oncology through the rational design of a multi-mechanistic combinatorial approach based on the underlying biology of the tumor microenvironment. By first gaining a better understanding of the immune-suppressive microenvironment in HCC and the immune modulatory responses to OV therapy in HCC, we aimed to rationally design a therapeutic regimen using a novel chimeric vector, VSV-NDV, as the basis for a cutting edge and broad-acting oncolytic viral vaccine. In this project, the VSV-NDV technology is used as a viro-immunotherapeutic platform for HCC, with further engineering to express an immune checkpoint-modulating gene to ameliorate the immune-suppression, while simultaneously activating the antitumor immune response via induction of immunogenic cell death through virus-mediated oncolysis. As an additional layer of therapy, a novel anti-cancer vaccine is under development, in which antigen presenting cells, called dendritic cells (DCs), are prepared in a unique manner, whereby they will be activated and loaded with antigens using VSV-NDV-infected tumor oncolysates ex vivo.
This multifaceted approach represents an innovative and crucial step forward revolutionizing immune oncology and providing new hope to cancer patients with immune-suppressive solid tumors.
Thus far, the ONCO-VAX project has yielded many interesting results related to the originally proposed work packages. A substantial portion of the work has focused on the evaluation of innate intracellular responses to infection with the hybrid VSV-NDV vector, modulatory effects in the tumor microenvironment in response to therapy, as well as elucidation of innate and adaptive immune responses. This work demonstrated that, in addition to the direct tumor cell killing elicited by VSV-NDV infection, modulation of the tumor microenvironment and induction of immune responses represent an important aspect of the therapeutic mechanism. Furthermore, the induction of immunogenic cell death and immune cell activation support the hypothesis that VSV-NDV could synergize with other immunotherapy approaches, such as immune checkpoint blockade and adoptive cell therapy.
To this end, preliminary data demonstrated that VSV-NDV could mediate systemic immune responses to control distant tumor growth, and these results could be further enhanced through combination with immune checkpoint inhibiting antibodies and with adoptive T cell therapy. As a next step, we also carried out viral engineering steps in order to incorporate a soluble PD1 protein into the VSV-NDV vector. With this approach, we aimed to disrupt inhibitory T cell signalling without the need for applying additional systemic antibodies, which are costly and are often associated with severe side effects. The new “armed” OV construct (named VSV-NDV-HAsPD1) was fully characterized in vitro, and preliminary in vivo analysis was also performed. Here, it was shown that VSV-NDV-HAsPD1 could provide enhanced tumor control compared to the parental VSV-NDV vector.
As a third arm of the project, we developed multiple assays and optimization steps to establish a dendritic cell (DC) vaccine based on VSV-NDV oncolysis of tumor material ex vivo. By co-culturing DCs with tumor cells that had been infected with VSV-NDV, we envisioned that the DCs would become optimally activated, while also taking up the wide range of tumor antigens released by the lysed tumor cells. To date, we have generated an optimized approach for preparing and loading the DCs and demonstrated that the approach leads to efficient DC activation and antigen presentation to cytotoxic T cells. As a next step, the approach will be characterized in vivo using various preclinical tumor models.
To this end, preliminary data demonstrated that VSV-NDV could mediate systemic immune responses to control distant tumor growth, and these results could be further enhanced through combination with immune checkpoint inhibiting antibodies and with adoptive T cell therapy. As a next step, we also carried out viral engineering steps in order to incorporate a soluble PD1 protein into the VSV-NDV vector. With this approach, we aimed to disrupt inhibitory T cell signalling without the need for applying additional systemic antibodies, which are costly and are often associated with severe side effects. The new “armed” OV construct (named VSV-NDV-HAsPD1) was fully characterized in vitro, and preliminary in vivo analysis was also performed. Here, it was shown that VSV-NDV-HAsPD1 could provide enhanced tumor control compared to the parental VSV-NDV vector.
As a third arm of the project, we developed multiple assays and optimization steps to establish a dendritic cell (DC) vaccine based on VSV-NDV oncolysis of tumor material ex vivo. By co-culturing DCs with tumor cells that had been infected with VSV-NDV, we envisioned that the DCs would become optimally activated, while also taking up the wide range of tumor antigens released by the lysed tumor cells. To date, we have generated an optimized approach for preparing and loading the DCs and demonstrated that the approach leads to efficient DC activation and antigen presentation to cytotoxic T cells. As a next step, the approach will be characterized in vivo using various preclinical tumor models.
Although exciting breakthroughs in cancer immunotherapy have raised hopes for transformative treatments, many solid cancers have proven to be relatively refractory to these approaches. The shortcomings of most immune-based therapies in solid cancers can be mostly attributed, either to the inherent properties of the tumor, which make them resistant to these approaches, or to the extreme specificity of the targeted approaches that fail to take into account the heterogeneity of the tumor. In order for immune-based therapies to be effective in these tumors, it is necessary to develop effective strategies to modulate the immune-suppressive tumor microenvironment. OVs can offer a novel approach to address challenging solid tumors by combining the benefits of direct tumor cell oncolysis with modulatory effects to break immune tolerance.
The central hypothesis of ONCO-VAX is that current challenges in the field of immune-oncology can be addressed through the rational design of a multi-mechanistic combinatorial approach based on the underlying biology of the tumor microenvironment. By first elucidating the immune landscape of solid tumors, like HCC, both before and as a consequence of VSV-NDV therapy, we aim to design our optimal combination dosing scheme in an informed manner, and thereby succeed, where most OV and immune-based therapeutics have failed. By the end of the project, we expect to have developed a multifaceted approach that optimally combines viral oncolysis to directly kill tumor cells, immune checkpoint blockade to release the “brakes” on the immune system, and vaccination to accelerate cytotoxic immune functions against a wide array of tumor antigens, in a rational and stepwise design. This strategy aims to attack the cancer from various angles, leaving it no option to escape, and represents a ground-breaking virus-based immunotherapy with a high potential for clinical translation.
Within the context of ONCO-VAX, we will fully characterize the immune cellular response to oncolytic VSV-NDV therapy in solid cancers, we will evaluate the efficacy of immune-checkpoint modulating next-generation vectors, and we will develop a completely novel DC vaccine approach that can be combined with our optimized OV therapy. The proposed approach will be fully developed and tested in preclinical mouse tumor models. This work will form the basis and proof-of-concept for translation of the approach to a human system for clinical application.
The central hypothesis of ONCO-VAX is that current challenges in the field of immune-oncology can be addressed through the rational design of a multi-mechanistic combinatorial approach based on the underlying biology of the tumor microenvironment. By first elucidating the immune landscape of solid tumors, like HCC, both before and as a consequence of VSV-NDV therapy, we aim to design our optimal combination dosing scheme in an informed manner, and thereby succeed, where most OV and immune-based therapeutics have failed. By the end of the project, we expect to have developed a multifaceted approach that optimally combines viral oncolysis to directly kill tumor cells, immune checkpoint blockade to release the “brakes” on the immune system, and vaccination to accelerate cytotoxic immune functions against a wide array of tumor antigens, in a rational and stepwise design. This strategy aims to attack the cancer from various angles, leaving it no option to escape, and represents a ground-breaking virus-based immunotherapy with a high potential for clinical translation.
Within the context of ONCO-VAX, we will fully characterize the immune cellular response to oncolytic VSV-NDV therapy in solid cancers, we will evaluate the efficacy of immune-checkpoint modulating next-generation vectors, and we will develop a completely novel DC vaccine approach that can be combined with our optimized OV therapy. The proposed approach will be fully developed and tested in preclinical mouse tumor models. This work will form the basis and proof-of-concept for translation of the approach to a human system for clinical application.