Dr Boris Minev, President of Medical and Scientific Affairs at Calidi Biotherapeutics speaks to DDW’s Reece Armstrong about the company’s approach to treating cancer.
RA: Could you give us an idea of your current pipeline?
BM: Calidi Biotherapeutics’ current pipeline consists of oncolytic virus-based immunotherapies potentiated by allogeneic stem cells and designed to treat patients for whom few, if any, effective treatment options exist. Our lead candidates are NeuroNova (NNV), which is being tested for the treatment of glioblastoma, and SuperNova (SNV), which is being tested for the treatment of metastatic solid tumours including melanoma, breast cancer, and head and neck cancers.
RA: How do oncolytic viruses work to attack cancer cells?
BM: Oncolytic viruses preferentially infect and replicate within cancer cells. Every oncolytic virus has its own molecular mechanism for targeting cancer cells, but some oncolytic viruses that are highly effective and produce minimal side effects lend themselves to therapeutic applications better than others. Oncolytic viruses may kill cancer cells by several mechanisms including virus replication-associated cell death (‘oncolysis’), induction of tumour-specific T lymphocytes, induction of bystander cell killing and by viral induction of changes in tumour-associated vasculature. As infected tumour cells disintegrate, they release additional copies of the tumour-killing virus into the tumour microenvironment, which go on to infect other cancer cells. Furthermore, the presence of viral particles and tumour cell fragments activates the immune system and primes it to attack any disparate cancer cells circulating in the bloodstream or at distant tumour metastases.
RA: What are the advantages of using oncolytic viruses to combat cancer?
BM: Oncolytic viruses specifically target cancer cells while leaving normal, healthy cells unharmed. As a result, these have enormous potential to be developed into highly effective therapies that are safe and well-tolerated by patients. Indeed, results from the previous Phase I clinical trials of SNV and NNV demonstrated that loading stem cells with oncolytic virus resulted in promising signals of efficacy via both direct lysis of the tumour cells as well as activation of an anti-tumour immune response. Both therapies also had excellent safety profiles.
RA: Why has it taken so long for oncolytic viruses to be used in oncology?
BM: While oncolytic viruses have been shown to efficiently kill cancer cells in a dish for many years, when they are administered as therapies, they are quickly eliminated by the patient’s immune system. In the past, when oncolytic virus therapies were delivered to patients in their naked form, and unprotected, they were quickly inactivated by the patient’s immune system before reaching target tumour cells. Calidi Biotherapeutics leverages an allogenic stem cell-based platform which protects the oncolytic virus from the patient’s immune system, like a trojan horse, shielding the virus until it reaches the cancer cells it is designed to infect and kill. This drives efficacy of our cell-based platform in three ways, a process called ‘potentiating’: It protects the virus from destruction by the patient’s immune system; it promotes amplification of the oncolytic virus and viral proteins inside the stem cells and upon reaching the tumour, it instantly modifies the tumour microenvironment leading to effective virus expansion and optimal tumour cell targeting.
RA: Are oncolytic viruses more beneficial in certain types of cancers than others?
BM: Calidi Biotherapeutics is currently testing its oncolytic viruses in solid tumours, where allogenic stem cells loaded with oncolytic virus can be injected directly into the tumour. Our therapies have been administered to patients with glioblastoma, metastatic unresectable melanoma, triple negative breast cancer (TNBC), and advanced metastatic squamous cell head and neck carcinoma (HNSCC) and acute myeloid leukaemia; however, oncolytic viruses are active against a wide range of other solid tumours and haematological malignancies, meaning that Calidi’s approach has the potential to be adapted for the treatment of virtually any cancer. Indeed, Calidi BioTherapeutic’s research has shown that practically all malignancies can be targeted. However, haematologic malignancies in general require higher drug dose than the solid tumours to achieve the same therapeutic effect.
RA: Could this type of treatment be used alongside other oncology therapies such a cell & gene therapies?
BM: Oncolytic viruses can be used in combination with other cancer treatments, including cell & gene therapies. Following the success of initial clinical trials of our NNV and SNV agents, Calidi Biotherapeutics plans to conduct clinical studies of these agents in combination with other immunotherapies, such as checkpoint inhibitors, which we believe will offer a synergistic therapeutic effect and carry non-overlapping toxicity profile.
RA: Could you describe the cell-based delivery system you’re using for these therapies?
BM: Calidi Biotherapeutics’ approach is more than just a delivery system: our strategy hides as well as amplifies the oncolytic viruses within stell cells. Additionally, by the time the oncolytic virus arrives at the tumour site, it is primed to deliver swift, intense anti-tumour activity. The biological composition of our therapies differs slightly: the SNV platform consists of mesenchymal stem cells gathered from fat tissue of healthy adult donors (via liposuction) and loaded with vaccinia virus. The virus is allowed to replicate within the cells, which are then frozen. Prior to injection, the cells containing the oncolytic viruses are thawed, then injected into the patient at the tumour sites. Our NNV platform uses a similar strategy, but instead consists of immortalised neural stem cells loaded with oncolytic adenovirus.
RA: You’ve released data on two small-scale studies in glioblastoma and solid tumours. How encouraged are you by the results and what are your plans to progress into further trials?
BM: We are very encouraged by the results of our initial Phase I clinical trials studying NNV and SNV in the clinic. While the idea of oncolytic virus therapy has been tried over many years, and has often failed to produce meaningful patient responses, the concept of hiding the virus inside stem cells is novel. Our initial studies found this approach to be safe, with signals of efficacy. We expect to see even better clinical efficacy results as we continue clinical studies of these products. Both NNV and SNV product scan be used to treat patients with limited treatment options.
Volume 23 – Issue 3, Summer 2022
