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

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CYNK-101 demonstrated synergistic activity when used in combination with avelumab through antibody-dependent cellular cytotoxicity against PD-L1–positive non–small cell lung cancer, triple-negative breast cancer, and bladder cancer cell lines, according to preclinical data.

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.

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“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


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