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Abstract
Background Oncolytic viral immunotherapy utilizes viruses that preferentially infect and replicate within cancer cells, resulting in both tumor cell destruction and activation of an anti-tumor immune response. However, a major obstacle to this approach has been the rapid oncolytic virus (OV) elimination by patient’s immune system. Calidi’s innovative platform combines allogeneic stem cells with an oncolytic virus payload, preventing immune system elimination of the OVs and promoting viral amplification at tumor sites. This approach induces immunogenic cell death of infected tumor cells and stimulates potent and durable anti-tumor immune responses, effectively targeting both primary and metastatic tumors. We demonstrated in a clinical study that patient’s own (autologous) stem cells loaded with OVs can be remarkably effective in multiple tumor types, especially in combination with checkpoint inhibitors. However, this approach is very costly and not scalable. Building on this work, we developed an innovative concept called ‘SuperNova-1’ (or CLD-201), based on OV-loaded allogeneic stem cells.
Methods Multiple allogeneic adipose tissue-derived mesenchymal stem cell banks were generated, and one was selected for GMP manufacturing and loaded with the oncolytic vaccinia virus CAL1, creating CLD-201. CLD-201’s ability to kill cancer cells in the presence of complement and neutralizing antibodies was assessed. Immune cell infiltration in treated and untreated tumors was analyzed by flow cytometry. Safety, toxicology, biodistribution studies, and GMP manufacturing of CLD-201 have been completed.
Results CLD-201 demonstrated greater resistance to inactivation by the humoral immune system compared to the unprotected CAL1 virus. CLD-201 significantly inhibited the growth of the tumors even at the very low dose of 1.5x103 cells containing 1.6x104 viral plaque forming units (PFU) and induced robust anti-tumor immunity in animal models. CLD-201 has been successfully GMP manufactured, and its safety profile has been analyzed in both immunocompetent and immunocompromised mouse models.
Conclusions CLD-201 offers several important advantages over the autologous approach, including enhanced potency through significant viral amplification within the stem cells, improved manufacturing reproducibility, off-the-shelf ability to treat multiple cancer types, and significantly lower cost. A phase I non-randomized clinical trial has been designed to evaluate the safety and initial anti-tumor effects of CLD-201, both as a monotherapy and in combination with checkpoint inhibitors. Additionally, multiple immune biomarkers will be assessed to measure the biological activity of CLD-201.
Ethics Approval The master cell bank was generated from Adipose-Derived Mesenchymal Stem Cells, protocol number AD-MSC1, and approved from Institute or Regenerative and Cellular Medicine(IRD). IRB approval number IRCM-2018–196. Blood was collected for analysis of immunological responses, protocol number CB-IR-002, and approved from Institute or Regenerative and Cellular Medicine(IRD). IRB approval number IRCM-2019–203. The protocols and consent form was approved by IRB and all donors have consented.
The stem cells were collected under IRCM IRB approved protocol number AD-MSC1 and the RID approval number is IRCM-2018–196.
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