Cytovia Exploring Multiple NK Cell Therapies Across Settings

Daniel Teper

Natural Killer (NK) cells have rapidly moved from a budding area of research into a highly promising new treatment class, with the most promising potential being demonstrated in various oncology settings. There are currently over 300 studies under way exploring NK cells in various disease settings, with new companies emerging that focus exclusively on this new treatment class of innate cells.

Presentations at the Jeffries Virtual Healthcare Conference highlighted advances made with this novel type of cell therapy, including early therapies being developed by Cytovia, a company founded specifically with the belief that NKs cells have the potential to revolutionize cancer immunotherapy towards a cure.

"Cytovia is the first company developing synergistic and proprietary platforms NK therapeutic platforms, including bi-specific NKp46 engager antibodies, iPSC [induced pluripotent stem cell]-derived universal NK cells, and gene edited iPSC NK cells, including CAR NK cells," Daniel Teper, co-founder, chairman, and chief executive officer at Cytovia, said during a presentation at the conference.

NK Cell Potential

NK cells are derived from the same progenitor cell as T and B cells and are members of the innate immune system. NK cells have grown in popularity in recent years for their demonstrated anti-tumor activity and the absence of common T cell-based therapy toxicity, such as cytokine release syndrome. Of the 300+ active trials exploring NK cells listed on clinicaltrials.gov, most are focused on the treatment of hematologic malignancies, primarily acute myeloid leukemia and T-cell lymphoma.

NK cells express several activating receptors, with one of the most promising for potential therapeutic implications being NKp46, which has commonly been seen in tumor infiltrating NK cells, as noted in Cell. In early studies it was shown that engaging NKp46 with antibodies led to NK cell-mediated antibody-dependent cellular cytotoxicity.

Cytovia’s Diversified Pipeline

In the Jeffries presentation, Cytovia detailed their process, which capitalizes on several established partnerships. The process starts with iPSCs obtained from the New York Stem Cells Foundation. These cells are edited in a reproducible method for any number of targets.

The company is beginning with GPC3, which was gained from a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute, EGFR through a relationship with CytoImmune, and CD38 from an agreement with INSERM. The editing is being conducted using the TALEN method, developed by Cellectis. After editing, the cells are differentiated into NK cells using a proprietary process. After differentiation, the cells are cryopreserved for shipment.

"The R&D collaboration with Cellectis is unique in that it allows us to use these validated TALEN meganucleuses to edit the iPSC NK cells. We have worldwide license to do so," Stanley Frankel, chief medical officer, Cytovia, detailed during the Jeffries presentation.

Using this methodology, Cytovia has developed a comprehensive pipeline of preclinical products. The company is exploring 2 classes of therapies, namely chimeric antigen receptor (CAR) modified NK cells and multi-specific NK engagers.

For GPC3, CYT-303 is an NKp46 and GPC3 NK engager with anticipated activity against hepatocellular carcinoma (HCC). The company anticipates an investigational new drug application (IND) for this agent in the first quarter of 2022. The second GPC3-specific therapy is a CAR NK cell labeled CYT-503, also being explored for HCC and other solid tumors. The GPC3 target was explored extensively by Mitchell Ho, PhD, chief of the Laboratory of Molecular Biology at the NCI Center for Cancer Research.

“Natural Killer cells play a major role in the immuno-surveillance of liver cancer. GPC3 is expressed in more than 70% of HCC cells but not on healthy cells," Ho said in a statement at the time of the CRADA. "We look forward to investigating whether GPC3 CAR-NK therapy could provide a new safe and effective off-the-shelf option for patients with liver cancer.”

Agents targeted against CD38 are being explored for hematologic malignancies, and with proven success established for this target in multiple myeloma. Cytovia is targeting an IND for their NK engager CYT-338 for study in myeloma and lymphoma in the second quarter of 2022. There is already an agreement in place, through the collaboration with INSERM, to explore this therapy at Hôpital Saint-Louis’ Research Institute.

"We have demonstrated the selectivity of our novel CD38 antibody in killing myeloma cells but not normal cells such as NK, T, and B cells," Armand Bensussan, PhD, director of The Immuno-Oncology Research Institute at Hôpital Saint-Louis, said in a statement when the agreement was established. "The activation of NK cells through NKp46 may enhance the efficacy of the bispecific antibody in patients not responsive to CD38 monoclonal antibody therapy. CD38 CAR NK is a promising approach for relapsed/refractory patients and an alternative to CAR T therapies."

The final target, EGFR, will be examined for glioblastoma multiform and other solid tumors. This agent, CYT-501, is a dual-targeted (EGFRvIII and EGFR wild-type) CAR NK-cells therapy and will be administered as an intracranial injection. The anticipated IND date for this therapy is in the second half of 2022.

“CAR NK cell therapy has the potential to transform cancer outcomes," Michael A. Caligiuri, MD, scientific founder of CytoImmune and Deana and Steve Campbell Physician in Chief Distinguished Chair and President of the City of Hope National Medical Center, said when the agreement was announced. "We are excited to partner with Cytovia to rapidly bring EGFR dual-targeting CAR NK cells, a next generation therapy, to patients with the ultimate goal of curing glioblastoma. Cytovia’s off-the-shelf iPSC CAR NK cell technology should increase the access to precision immunotherapy for many cancer patients.”

In addition to these therapies, Cytovia is also developing 2 universally edited NK cell therapies, namely CYT-100 and CYT-150. INDs for these therapies, which will be explored in solid tumors in combination with NK cell engagers and/or immune checkpoint inhibitors, is set for the first quarter of 2022.

"We have a differentiated pipeline with multiple first-in-class therapeutic candidates. Our 2 priority franchises are GPC3 in solid tumors, with both engagers NK cells and CAR NK cells, and CD38 in hematology, specifically in multiple myeloma, against with NK cell engagers and NK CARs," Teper said.

To support the clinical trials anticipated by the INDs, Cytovia has a research and development facility in Massachusetts and has established GMP manufacturing infrastructure in Puerto Rico. Moreover, in addition to the NCI, the company has established relationships with UCSF and City of Hope for development. "In 2022, we're bringing to the clinic products to 3 validated targets where we're positioned to be first in class," Teper added.

Cytovia is planning for an initial public offering by the end of 2021.