CYNK-101 Plus Avelumab Mediates ADCC Activity in Select PD-L1+ Solid Tumors

CYNK-101 demonstrated synergistic activity when used in combination with avelumab (Bavencio) through antibody-dependent cellular cytotoxicity against PD-L1–positive non–small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and bladder cancer cell lines, according to preclinical data presented at the 2022 SITC Annual Meeting.¹

When administered in combination with the PD-L1 inhibitor at 0.1 μg/ml, CYNK-101 secreted higher levels of interferon-gamma and GM-CSF against the NSCLC cell line NCI-H1975 and the TNBC cell line MDA-MB-231. It also increased GM-CSF against the bladder cancer cell line RT-112.

Specifically, greater than 92% (CD56+/CD3-) purity was achieved, 65% to 88% CD16 expression was maintained post thaw, and CD16 was resistant to being cleaved from the surface following NK cell activation.

“CYNK-101 cells provide a combination immunotherapy option by harnessing the antitumor activities of both targeted biologics and innate cytotoxicity of [natural killer] cells,” lead study author and principal investigator Irene Raitman, and coinvestigators wrote in the poster presented during the meeting. “Further development of CYNK-101 in combination with the therapeutic antibody for these solid tumor indications is warranted.”

CYNK-101 is manufactured from human placental hematopoietic stem cells, which are genetically modified to express a high-affinity and cleavage-resistant CD16 variant (FCGRIIIA). Beyond innate NK cell functions, CYNK-101 is meant to support ADCC when used in combination with other tumor-targeted monoclonal antibodies.

In the study presented at the 2022 SITC Annual Meeting, investigators evaluated the ADCC activity of CYNK-01 combined with avelumab in PD-L1–positive NSCLC, TNBC, and bladder cancer tumor cells.

For the process, human placental CD34-positive cells were transduced with a lentivirus vector expressing the CD16 variant and cultured in the presence of cytokines to generate CYNK-101 cells. CYNK-101 cells were frozen upon completion of cell expansion and differentiation. Furthermore, the CYNK-101 cells were evaluated for CD56, CD3, and CD16 via flow cytometry after being thawed.

Investigators assessed antitumor activity of CYNK-101 cells against PD-L1–positive NSCLC cell line NCI-H1975, TNBC cell line MDA-MB-231, and bladder cancer cell lines RT-112, 5637, and T-24. ADCC activity was measured through the real-time xCELLigence assay and cytokine secretion was assessed by Luminex xMAP multiplex assay. Wortmannin was utilized to study molecular mechanisms underlying cytotoxicity of CYNK-101 cells against the lung cancer cell line.

Four-hour and 24-hour ADCC activity of CYNK-101 with avelumab on the cells were evaluated. Additionally, investigators noted the high expression and cleavage resistance of CD16 on CYNK-101, and PI3K pathway inhibition also decreased CYNK-101 in combination with avelumab ADCC.

In February 2022, the FDA granted an orphan drug designation to CYNK-101 as a potential treatment for patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to Celularity, the developer of the allogeneic cell therapy.²

The treatment is currently being investigated in combination with standard frontline chemotherapy, trastuzumab (Herceptin), and pembrolizumab (Keytruda) for patients with HER2-positive gastric and GEJ cancer in a phase 1/2a study (NCT05207722).

In January 2022, the FDA granted CYNK-101 a fast track designation for this combination,³ which was preceded in November 2021 by the approval of an investigational new drug application for the off-the-shelf therapy.⁴

References

1. Raitman I, Foley G, He E, et al. Developing placental CD34+-derived natural killer cells with high affinity and cleavage resistant CD16 (CYNK-101) in combination with Avelumab for enhanced therapy against PD-L1–positive solid tumors. Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 270.
2. Celularity receives orphan drug designation from U.S. FDA for its NK cell therapy CYNK-101 in development for the first-line treatment of advanced HER2/neu positive gastric and gastroesophageal junction cancers. News release. Celularity. February 15, 2022. Accessed November 11, 2022. https://bit.ly/3GWIpBw
3. Celularity receives fast track designation from U.S. FDA for its NK cell therapy CYNK-101 in development for the first-line treatment of advanced HER2/neu positive gastric and gastroesophageal junction cancers. News release. Celularity. January 18, 2022. Accessed November 11, 2022. https://bit.ly/3tyy3Vv
4. Celularity announces FDA clearance of investigational new drug application (IND) for natural killer cell therapy CYNK-101 in first-line advanced HER2/neu positive gastric and gastroesophageal junction cancer. News release. Celularity. November 29, 2021. Accessed November 11, 2022. https://bit.ly/3WYEo8M