Shielding Oncolytic Viruses From the Immune System To Improve Cancer Treatment
Immunotherapy is a method of treatment that attempts to harness the power of the immune system to prevent, target and treat cancer. One such approach, oncolytic virus (OV) therapy – whereby viruses are modified to attack cancer cells – can be used to lyse cancer cells and induce anti-tumor immune responses through the release of antigens (tumor and viral) into the tumor microenvironment. While OVs have garnered increasing attention from the cancer research community, this therapeutic strategy doesn’t come without its challenges, as a patient’s immune system can sometimes mount a response to the OVs before they reach their intended target.
To address this, Calidi Biotherapeutics has developed cell-based platforms to shield OVs from the immune system, so that they can effectively target and destroy the cancer cells.
Technology Networks spoke with Dr. Boris Minev, president of medical and scientific affairs at Calidi Biotherapeutics, to learn more about the company’s new allogeneic cell-based technologies and how they can be used to tackle treatment-resistant cancers. In this interview, Minev also tells us more about the benefits and limitations to using OVs and highlights some of the success stories they have already seen with their platforms.
Zoe Braybrook (ZB): How are Calidi’s stem cell-based technologies able to tackle cancers, and other therapy-resistant diseases, that have previously proven unresponsive to treatments available currently?
Boris Minev (BM): According to BioCentury’s November 2021 report, there are at least 49 OV therapies in the clinical pipeline. Yet, after decades of research, OVs have yet to successfully revolutionize oncology. Past strategies utilized unprotected OVs that were quickly eliminated by the patient’s immune system, resulting in very limited therapeutic potential. Therefore, our approach is a Trojan horse strategy that utilizes stem cells to protect the OVs from inactivation by the body’s immune system. This allows the virus to begin replication and gene expression inside the stem cells before it’s delivered, effectively transforming the tumor microenvironment and inducing an anti-tumor response upon delivery. This multifaceted anti-tumor activity makes our therapies powerful tools against treatment-resistant cancers. Moreover, our drug products can be administered alone or in combination with other immunotherapies, such as checkpoint inhibitors, to enhance the effect of these treatments.
ZB: How is it that OVs kill cancer cells and what makes them so effective?
BM: OVs preferentially infect and kill cancer cells, but the molecular mechanisms that they use to target cancer cells vary from species to species. The therapeutic efficacy of OVs is achieved through selective amplification of the virus inside the cancer cells, which causes the tumor to disintegrate, subsequently promoting immune stimulation through the release of tumor and viral antigens in the tumor microenvironment.
Preclinical data has shown Calidi’s SuperNova-1 (SNV1) product to shield the OV from a patient’s immune system, supporting efficient delivery to tumor sites and effectively potentiating the viral payload. The Calidi Biotherapeutics SuperNova platform leverages allogeneic stem cells loaded with oncolytic vaccinia virus. Our cell-based platform protects the virus and drives efficacy in three ways, a process called “potentiating”:
- Prevents the viral elimination by the patient’s immune system
- Amplifies the OVs and viral proteins inside the stem cells
- Instantly modifies the tumor microenvironment leading to effective virus expansion and optimal tumor cell targeting
Laura Lansdowne (LL): What are the benefits of using OVs to treat cancer, compared to other immunotherapeutic approaches?
BM: OV therapy utilizes viruses that preferentially infect and replicate within cancer cells, resulting in both direct lysis of the diseased cells as well as activation of an anti-tumor immune response, while leaving normal, healthy cells unharmed. They may kill cancer cells by several mechanisms including virus replication-associated cell death (“oncolysis”), induction of tumor-specific T cells, induction of bystander cell killing and by viral induction of changes in tumor-associated vasculature.
LL: Can you touch on the limitations/challenges related to existing first-generation OV-based treatments?
BM: The body’s own immune system is the biggest challenge. OV therapy has been pursued by multiple companies and institutions with few candidates reaching the clinic and demonstrating limited efficacy. That’s because the therapeutic potential of OVs can be severely restricted by innate and adaptive immune barriers.
Therefore, our work is to outsmart the immune system so that the virus can be effectively delivered to the tumor sites. These three benefits of Calidi’s platform for potentiating (referenced above) enable the detection and destruction of tumors. Calidi scientists are constantly refining this approach by improving the virus-loading processes, stem cell expansion, virus expansion and the applicability of Calidi’s products for systemic delivery.
ZB: How are you using NeuroNova (NNV) and SuperNova (SNV) to overcome these obstacles, can you tell us more about each of these stem cell-based delivery platforms?
BM: Calidi Biotherapeutics has two proprietary, differentiated stem cell-based platforms NeuroNova (NNV) and SuperNova (SNV) – each with large target markets in areas of highly unmet need. In contrast to first-generation OV-based treatments, our platforms are designed to overcome patients’ immune defense mechanisms to deliver the OV payload. A major benefit of the intratumoral strategy is that it delivers our therapy directly to the tumor site yet shows efficacy at distant metastatic sites by activating T cells throughout the body.
NeuroNova (NNV) is an allogeneic therapy composed of immortalized neural stem cells (NSC) loaded with oncolytic adenovirus.
- Indication: Glioblastoma (GBM), an aggressive cancer in the brain or spinal cord.
- Clinical trial: Open-label, Phase 1, dose-escalation clinical trial in patients with newly diagnosed high-grade gliomas has been completed, establishing the safety and signals of efficacy in patients with newly diagnosed glioblastoma (GBM). Treatment was injected directly into the surgical margin after tumor resection.
- Published data: Clinical trial results were published by Fares et al. in Lancet Oncology.
SuperNova (SNV) is composed of adipose-derived mesenchymal stem cells (AD-MSC) loaded with oncolytic vaccinia virus.
- Indication: Advanced solid tumors.
- Clinical trial (SNV-0): A physician-sponsored Phase 1 clinical trial was completed using patients’ own autologous, adipose-derived stromal cells loaded with oncolytic vaccinia virus. Treatment was delivered systemically and intratumorally. Results documented excellent safety and signaled efficacy in 24 patients with advanced solid tumors and two patients with acute myeloid leukemia (AML).
- Published data: Clinical trial results were published by Minev et al. in The Journal of Translational Medicine.
- Additional studies: Upcoming trial (SNV-1), allogeneic adipose-derived mesenchymal stem cells carrying oncolytic vaccinia virus will be delivered intratumorally to target triple-negative breast cancer, advanced squamous cell head and neck cancers, and unresectable/metastatic melanoma. Current preclinical studies of the systemic delivery SuperNova platform are also underway.
ZB: From the results of previous clinical trials it appears you have already had some success with both NNV and SNV, are there any other success stories that you would like to share with us?
BM: We’re particularly proud of our work with the National Institute of Health (NIH), as part of our ongoing pre-clinical collaboration to examine and compare how the progression of vaccinia virus infection in the carrier stem cells, adipose-derived and bone marrow stem cells, might differentially change their intrinsic immunomodulatory capacity. Subsequently, we identified the advantages of adipose-derived stem cells, including less invasive procedures to obtain, larger starting numbers of stem cells, better scale-up and higher suitability for commercial use.
We are currently engaged in the discovery of next-generation product candidates such as SNV2 and AAA1. For example, SNV2 is based on engineered oncolytic vaccinia virus constructs with specific payloads, such as antibodies, checkpoints, or others, designed to increase the tumor specificity and oncolytic potency. Calidi’s AAA1 stem cells were successfully used in a clinical trial in patients with COVID-19. According to clinical trial preliminary data, three intravenous infusions of Calidi’s stem cells were safe and showed initial signs of efficacy in treating patients with advanced COVID-19.
Dr. Boris Minev was speaking with Zoe Braybrook, Content Marketing Executive and Laura Elizabeth Lansdowne, Managing Editor at Technology Networks.