Sorrento Therapeutics, and its cellular therapy focused subsidiary, TNK Therapeutics, (TNK), have announced the results from the Hepatic ImmunoTherapy for Metastases-Selective Internal Radiation Therapy, or HITM-SIR (NCT02416466), Study, a Phase Ib single arm trial testing its anti-CEA CAR-T administered regionally by hepatic artery infusion (HAI) followed by selective internal radiation therapy (SIRT) in heavily pre-treated patients with CEA positive liver metastases.  This Phase Ib trial follows the Hepatic ImmunoTherapy for Metastases, or HITM (NCT01373047) Phase I study which demonstrated the safety and biological activity of the anti-CEA CAR-T administered with HAI alone.

The data of HITM-SIR were presented by Dr. Steven Katz, the Principal Investigator of the study and Associate Professor of Surgery at The Roger Williams Medical Center (CharterCare Health Partners and Prospect Medical Holdings) in a poster session at the 2017 American Association of Cancer Research (AACR) Annual Meeting in Washington DC.

HITM-SIR enrolled 8 patients with unresectable, chemotherapy refractory CEA+ liver metastases. Two patients were withdrawn, one for disease progression prior to CAR-T infusion and another for biliary obstruction due to centrally located disease. Subjects received three HAI of anti-CEA CAR-T cells (1e10 cells per dose) along with a low dose IL-2 infusion (50,000 IU/kg/day, Proleukin, Prometheus). SIRT with SIR-Spheres (Sirtex, funding sponsor) was administered in standard fashion 2 weeks following the third CAR-T HAI. The primary objective of the study was to establish the safety of the CAR-T/SIRT combination. Secondary objectives included response assessed by modified RECIST (mRECIST), immune-related response criteria (irRC), and tumor marker kinetics.

Providing the HITM-SIR study findings, Dr. Katz reported that six patients with unresectable, chemotherapy refractory colon, rectal and pancreatic cancer with CEA+ liver metastases had completed the protocol.  Prior to the study, these patients had received an average of 2.3 lines of prior chemotherapy and three of the six patients had 10 or more liver metastases. At completion of the study, 50% of the patients had stable disease in the liver by mRECIST and irRC as well as stable disease overall by irRC. The decrease in size of liver lesions among patients with stable disease ranged from 6-28%. Abscopal effects, namely regression of extrahepatic tumors at lung and bone sites, were noted in two of the six patients. The mean overall survival time for all patients as of the March 28, 2017 cutoff date was 7.5 months (range 15-50 weeks) and the median overall survival time was 6.9 months.  In comparison, the median overall survival time following regorafenib monotherapy in previously treated, chemotherapy refractory metastatic colorectal cancer patients is 6.4 months vs. 5 months for best supportive care, as reported in the Phase III CORRECT trial.

Dr. Katz noted, "One out of the six patients remains alive without evidence of liver disease at 10.8 months of follow-up. Importantly, after being treated with HITM-SIR, this previously unresectable, heavily pretreated patient successfully underwent resection of his primary tumor and reversal of his colostomy. In addition, one patient from our initial HITM phase I study remains alive for more than 4 years (50 months). After achieving disease control with treatment of the anti-CEA CAR-T, this previously refractory patient underwent microwave ablation of residual liver disease and received further systemic therapy. These outcomes are clinically meaningful in terms of the individual survival times and quality of life enhancement. Anti-CEA CAR-T HAI may represent a safe and well tolerated component of novel multi-modality regimens capable of meaningful disease control."

In addition, from a safety standpoint, the HITM-SIR protocol was well tolerated. There were no Grade 4 or Grade 5 events related to the anti-CEA CAR-T, SIRT, or the combination. Toxicities included Grade 1 and Grade 2 liver function test elevations (n=5/6), fever (n=5/6), hypereosinophilia (n=2/6), and edema (n=2/6). Grade 3 toxicities included colitis (n=2/6), fever (n=2/6), and edema (n=2/6). All colitis episodes resolved with IL-2 dose reductions.  

"The stabilization of disease rates that we are seeing with our anti-CEA CAR-T therapy in this heavily pre-treated and refractory metastatic population, at a well-tolerated dose, is very encouraging," said Jerome B. Zeldis, M.D., Ph.D., Chief Medical Officer of Sorrento Therapeutics. "The potential for our anti-CEA CAR-T therapy to stabilize metastatic disease to a point where the primary tumors can become resectable or liver failure can be delayed would significantly advance our therapeutic options. Furthermore, we now have treated 12 patients with our anti-CEA CAR-T and only observed mild to moderate side effects, suggestive of a good overall safety profile.  We look forward to completing an ongoing follow-up phase Ib trial testing an enhanced delivery system (NCT02850536), and designing a phase II trial for our anti-CEA CAR-T with Roger Williams Cancer Center."