Immunotherapy is a technique of treatment that attempts to harness the power of the immune system to prevent, target, and treat cancer. One such approach, oncolytic virus therapy, where viruses are modified to target cancer cells, can be used to induce anti-tumor immune responses, along with anti-tumor vaccinations. While OVs have received increasing attention from the cancer research community, this therapeutic approach does not come without challenges, as a patients immune system may re-acquaint them to their intended goal.
Calidi Biotherapeutics has developed cell-based systems to protect OVs from the immune system, so that they can effectively target and destroy the cancer cells.
How are Calidis stem cell-based therapies capable of combating cancers and other therapy-resistant diseases, according to Zoe Braybrook?
According to BioCenturys in November 2021, there are at least 49 OV therapies in the clinical pipeline. However, previous interventions delivered unprotected OVs that were quickly eliminated by the patient immune system, resulting in very limited therapeutic potential. Our therapeutic strategies are a Trojan horse approach that involves stem cells to accelerate replication and gene expression before they are delivered, effectively transforming the tumor microenvironment and inducing an anti-tumor response. Moreover, our drug products can be administered alone or in combination
ZB: How is it that OVs kill cancer cells, and what makes them so powerful?
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 effect of OVs is achieved by selective amplification of the virus inside the cancer cells, which causes the tumor to disintegrate, then promoting immune stimulation by the release of tumor and viral antigens in the tumor microenvironment.
Preclinicaldata has shown that the Calidis SuperNova-1 (SNV1) product will shield the OV from a patients immune system, leading to effective delivery to tumor sites and boosting the viral payload. Our cell-based platform, which integrates allogeneic stem cells with the oncolytic vaccinia virus, has demonstrated effectiveness in three ways.
Laura Lansdowne (LL): What are the benefits of using OVs to treat cancer, comparative to other immunotherapeutic therapies?
OV therapy utilises viruses that preferentially infect and replicate within cancer cells, resulting in direct lysis of the diseased cells as well as activation of an anti-tumorimmune response, while leaving normal, healthy cells unharmed. They may kill cancer cells by several strategies, including virus replication-associatedcell death (oncolysis), induction of tumor-specificT cells, induction of bystander cell killing, and by viral induction of changes in tumor-associatedvasculature.
Can you talk about the limitations/problems that may arise from existing first-generation OV therapies?
The body''s own immune system is the biggest challenge. Many businesses and institutions have pursued OV therapy, with few applicants reaching the clinic, demonstrating limited effectiveness. That is because the therapeutic potential of OVs can be severely hampered by innate and adaptive immune barriers.
Our aim is to outsmart the immune system so that the virus can be delivered to the tumor microsite. Calidi scientists are constantly refineting this approach by improving the virus-loading process, stem cell expansion, virus expansion, and the applicationability of Calidis products for systemic delivery.
ZB: How are you using NeuroNova (NNV) and SuperNova (SNV) to overcome these obstacles, and can you show us more about each of these stem cell-based delivery platforms?
Calidi Biotherapeutics has two proprietary, differentiated stem cell-based therapies NeuroNova (NNV) and SuperNova (SNV), each with large target markets in areas of unmet need. Contrary to the first-generation OV-based therapies, our platforms are designed to overcome patient immune defense mechanisms to deliver the OV payload. The intratumoral technique works directly to the tumor site, but it shows effectiveness at distant metastatic sites by activating T cells throughout the body.
The neuronova (NNV) is a non-invasive neuronova therapy composed of immortalized neural stem cells (NSC) that is loaded with an 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. inLancet Oncology.
SuperNova (SNV) is made of adipose-derived mesenchymal stem cells (AD-MSC) equipped with the oncolytic vaccine.
- 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 previous clinical trials, it appears you have achieved both NNV and SNV successes, and do you wish to share some additional success stories with us?
We are very proud of our collaboration with the National Institute of Health (NIH) as part of our ongoing pre-clinical work to examine and compare how the progression of vaccinia virus infection in the carrier cells might differ from its intrinsic immunomodulatory capacity. Consequently, we presented benefits and findings that included shorter beginning numbers of stem cells, improved scale-up, and more suitable for commercial use for bone marrow and adipose-derived.
The US Food and Drug Administration (FDA) has approved three intravenous injections of Calidis stem cells to treat COVID-19 patients. According to clinical trials, three intravenous injections of Calidis stem cells improved the effectiveness of treatments.