On March 5, 2018 Sorrento Therapeutics, Inc. (NASDAQ:SRNE) ("Sorrento"), cellular therapy focused subsidiary, TNK Therapeutics, Inc. ("TNK"), and Surefire Medical, Inc., reported initial results from the Hepatic ImmunoTherapy for Metastases-Surefire, or HITM-SURE (NCT02850536), a Phase 1b single arm trial testing its autologous anti-CEA CAR-T cells administered regionally by hepatic artery infusion (HAI) via pressure directed microvalve infusion (MVI) technology (Surefire Infusion System, Surefire Medical, Inc., Westminster, Colorado) in heavily pre-treated patients with refractory CEA-positive liver metastases (LM) (Press release, Sorrento Therapeutics, MAR 5, 2018, View Source [SID1234532251]). This Phase 1b trial follows the HITM (NCT01373047) and HITM-SIR (NCT02416466) Phase 1 studies we believe demonstrated the safety and biological activity of the anti-CEA CAR-T administered with hepatic artery infusions (HAI) alone or with selective internal radiotherapy.
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The data of HITM-SURE were provided 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). The study is also open at Colorado University and funded in part by the Colorado Office for Economic Development and International Trade.
In total, three patients have completed the ongoing HITM-SURE protocol, two with stage IV pancreatic cancer and one with colorectal cancer (LM). All patients presented with unresectable, chemotherapy refractory CEA+ liver metastases. Patients received three HAI of anti-CEA CAR-T cells (1e10 cells per dose) along with low dose IL-2 infusion (50,000 IU/kg/day, Proleukin, Prometheus). CAR-T HAI were administered via a Surefire MVI technology. The primary objective of the study was to establish the safety of the CAR-T HAI with the pressure directed MVI device. Secondary objectives included response assessed by modified RECIST (mRECIST), immune-related response criteria (irRC), and tumor marker kinetics. Reduction in post-treatment serum CEA was noted in all patients (average change 19 ng/mL, range 3.1-39 ng/mL). Two patients have progressive disease, with a pancreatic cancer patient alive at 7 months and a colorectal cancer patient alive at 4.8 months. A patient with stage IV pancreas adenocarcinoma has no evidence of liver metastases 11 months on PET scan following three CAR-T HAIs. In the phase III MPACT study, treatment of stage IV pancreas adenocarcinoma patients with gemcitabine plus albumin-bound paclitaxel resulted in a median overall survival time of 8.7 months. It will be of interest to determine if the results from upcoming phase 2 liver metastasis HITM studies will confirm the encouraging results from our small number of patients.
The initial findings from the currently enrolling HITM-SURE trial follows the results of two other trials. In one of the previous trials, a patient survived 51 months following 3 anti-CEA CAR-T HAIs and a patient from another trial is alive 25 months after treatment.
Dr. Katz noted, "In 15 patients in the Phase 1 and 1b studies, our CAR-T hepatic artery infusion method has resulted in highly selective delivery of CAR-T to liver tumors, with avoidance of severe cytokine release syndrome and neurotoxicity. We have observed encouraging clinical outcomes in heavily pre-treated patients. Future trials will test our novel delivery strategies for pancreatic and peritoneal tumors, in addition to novel combinatorial approaches to reverse organ-specific immunosuppressive pathways. We have developed a pipeline and delivery methods specifically tailored to address barriers to effective solid tumor CAR-T therapy, including the use of Surefire’s pressure-directed microvalve infusion technology to help overcome the high interstitial pressure of these tumors. The combination of CAR-T cells and this novel delivery mechanism are powerful tool for enhancing solid tumor uptake of CAR-T cells. Regional delivery of CAR-T cells has promise to be an important component of a multifaceted approach for advanced solid tumor patients."
"It is gratifying to observe that local infusion of CAR-T cells is very well tolerated and active in treating solid tumor metastases in the liver," said Dr. Jerome Zeldis, Sorrento Chief Medical Officer and President of TNK Therapeutics. "Based on these exciting data, we are now working on strategies to enhance the anti-solid tumor activity while lessening the complications typical of CAR-T therapy. In addition, we are planning on performing combination therapy studies using our CAR-T programs, including anti-CEA CAR-T, together with other Sorrento assets, such as our immuno-oncology checkpoint antibodies as well as Seprehvir, our clinical-stage oncolytic virus. The combination studies of anti-CEA CAR-T and Seprehvir should initiate the second half of 2018."