IND Accepted for HER2+ Gastric and Gastroesophageal Junction Cancer Cell Therapy

The FDA has accepted the investigational new drug (IND) application of Celularity’s natural killer (NK) cell therapy CYNK-101 for the potential first-line treatment of advanced HER2+ gastric and gastroesophageal junction cancer.¹

The engineered NK therapy will be evaluated for safety and preliminary efficacy in a phase 1/2a clinical trial in combination with standard chemotherapy, trastuzumab and pembrolizumab. The therapy is designed to enhance antibody-dependent cellular cytotoxicity (ADCC) when used in combination with these therapies.

“Gastric cancer represents the fifth most common cancer worldwide, and in advanced stages of the disease, continues to be associated with less than desirable survival outcomes despite recent advances,” said Robert Hariri, MD, PhD, founder, chairperson and chief executive officer, Celularity, in a statement.¹ “By enhancing the innate ADCC activity of our placental-derived NK cells, we have developed a cellular therapy platform that holds promise to complement and synergize with a range of antibody treatment strategies across a variety of tumor types. Our goal is to combine the potential advantages of placental-derived cellular therapies, including enhanced persistence, proliferation and resistance to cell exhaustion, with approved treatment strategies."

Preclinical data on CYNK-101 in HER2+ gastric cancer cells were presented at the American Association for Cancer Research (AACR) Annual Meeting, April 10-15, 2021, by Lin Kang, PhD, executive director, Celularity.² These data showed that ex vivo-CYNK-101 plus Trastuzumab exhibited enhanced cytotoxicity against NCI-N87 compared to IgG control. And also exhibited CD16 shedding resistance. In vivo anti-tumor ADCC activity was assessed in a mouse model and significant tumor reduction was observed in animals treated with CYNK-101 plus Trastuzumab compared to vehicle control, Trastuzumab or CYNK-101 alone (P <0.0001).

READ MORE: Celularity Cements Focus on Placenta-Derived Cell Therapies

“Among patients with locally advanced unresectable or metastatic HER2/neu positive gastric or gastroesophageal junction adenocarcinoma, advances in patient outcomes have been achieved with the addition of trastuzumab, and more recently, pembrolizumab, to standard chemotherapy, leading to regulatory approval of this combination. We are now excited to begin assessing if our off-the-shelf allogeneic placental-derived NK cells that have been genetically modified to enhance ADCC and resist cleavage of CD16 can improve clinical outcomes when added to the current combination in this patient population, Andrew Pecora, MD, president, Celularity, added to the statement.¹

The FDA previously approved trastuzumab (Enhertu, AstraZeneca and Daiichi Sankyo Company) in January 2021, and pembrolizumab (Keytruda, Merck & Co.) in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy in May 2021 for HER2+ gastric and gastroesophageal junction cancer.^3,4 

CYNK-101 also recently showed promising anti-tumor activity in combination with cetuximab for EGFR+ lung cancer and head and neck squamous cell carcinoma (HNSCC) in preclinical studies, with data presented at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), November 10-14, 2021 by Irene Raitman Khutorskoy, PhD, principal scientist, Celularity.⁵ 

Khutorskoy and colleagues observed anti-tumor activity by CYNK-101 with cetuximab in vitro.⁶ They found that CYNK-101 had greater cytotoxicity with cetuximab than with control in cultured cell lines (P <.05). Analysis with Wortmannin also revealed that CYNK-101's cytotoxicity is PI3K pathway-dependent. Investigators concluded that further development of CYNK-101 in this indication is warranted.

REFERENCES

1. 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. https://www.globenewswire.com/news-release/2021/11/29/2342134/0/en/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-Gastroe.html
2. Kang L, He S, Raitman I, et al. Potent immunotherapy of human placental CD34+-derived natural killer cells with high affinity and cleavage resistant CD16 (CYNK-101) plus Trastuzumab for HER2+ gastric cancer. Presented at: AACR 2021, April 10-15. Abstract 58.
3. Enhertu approved in the US for the treatment of patients with previously treated HER2-positive advanced gastric cancer. News release. AstraZeneca. January 18, 2021. https://www.astrazeneca.com/media-centre/press-releases/2021/enhertu-approved-in-the-us-for-gastric-cancer.html
4. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) combined with trastuzumab and chemotherapy as first-line treatment in locally advanced unresectable or metastatic HER2-Positive Gastric or gastroesophageal junction adenocarcinoma. News release. Merck. May 5, 2021. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-combined-with-trastuzumab-and-chemotherapy-as-first-line-treatment-in-locally-advanced-unresectable-or-metastatic-her2-positive-gastric-or-g/
5. Celularity presents preclinical data on allogeneic genetically-modified natural killer cells at the Society for Immunotherapy of Cancer 36th Annual Meeting. News release. Celularity. November 15, 2021. https://celularity.com/celularity-presents-preclinical-data-on-allogeneic-genetically-modified-natural-killer-cells-at-the-society-for-immunotherapy-of-cancer-36th-annual-meeting/
6. Raitman I, Fitzgerald J, Rousseva V, et al. Developing placental CD34+-derived natural killer cells with high affinity cleavage resistant CD16 (CYNK-101) and Cetuximab for enhanced therapy of EGFR+ non-small cell lung and head and neck cancers. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstract 159