T-Cell Therapy and Lymphodepletion in CAR Demonstrate Early Activity in Advanced Sarcoma

Shoba Navai, MD

In the Phase I findings presented at the 2019 AACR annual meeting, CAR T cell therapy and HER2-centered lymphoepithelative chemotherapy were found to be safe and effective as a treatment for adult patients and children with advanced HER2-positive sarcoma.

The trial (NCT00902044) included 10 patients with refractory / metastatic HER2-positive sarcoma treated with the CAR HER2-based T-cell product. CAR T cells developed in all patients except 2; the peak of median expansion was the seventh day (range, 5-28) and CAR T cells were detected by quantitative polymerase chain reaction in all patients 6 weeks after infusion.

"HER2 CAR T cells can be safely badociated with lymphodepletion; lymphodepletion enhances the expansion and persistence of T cells, "said study lead author Shoba Navai when presenting the results at the AACR meeting. "HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and the commitment of endogenous immunity may contribute to the generation of a tumor response."

Osteosarcoma, one of the most common types of sarcoma, is said to be HER2 positive in up to 40% of patients; In addition, this HER2-positive subtype is badociated with a higher probability of tumor metastasis. Preclinical data demonstrated that HER2-targeted therapy, including trastuzumab (Herceptin), is much less effective in sarcomas than in HER2-positive bad cancers.

"Children and adults with recurrent or refractory sarcomas have limited treatment options," said Navai, badistant professor of pediatrics at the Center for Cell Therapy and Genetics.
Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital. "Depending on the type of sarcoma, therapeutic regimens of curative rescue chemotherapy
are available, but the chances of success are low and the treatments can be quite toxic. "

However, HER2-directed CAR T cells have the ability to target low levels of HER2 on tumor cells compared to trastuzumab, as has also been found in preclinical studies, Navai explained. The CAR T molecule used in the phase I study comprises a HER2 binding domain, derived from an FRP5-derived antibody, linked to the signaling domain of a T lymphocyte containing CD28 co-stimulation.

In the trial, the investigators recruited 10 patients with osteosarcoma (n = 5), rhabdomyosarcoma (n = 3), Ewing's sarcoma (n = 1) and synovial sarcoma ( n = 1). A patient with rhabdomyosarcoma who enlisted and relapsed, then re-enrolled and withdrew. The median age was 14 years (range: 4-54 years) and up to 5 previous rescue therapies were administered.

Patients received up to 3 infusions of HER2-targeted autologous CAR T cells at 1 x 10⁸/ m² Amd lymphodepletion of fludarabine alone at 25 mg / m² per day (n = 3) or in combination with cyclophosphamide 30 mg / kg daily (n = 8). Both lymphodépletion patterns induced lymphopenia with an absolute number of lymphocytes <100 / ml on the day of T cell infusion and a fludarabine / cyclophosphamide inducing neutropenia up to 14 days. Patients were followed for a 6-week safety period, after which repeated badessments of the disease were made.

Those who had an initial response to these treatments then received a new infusion of CAR T cells, but without lymphodepletion.

The results also showed that at the end of the initial 6-week period, 4 patients had progressive disease and 4 patients had stable disease, the latter having lasted from 3.4 months to 9 months, Navai said. during his presentation.

"Five in ten patients were alive at the last follow-up and the overall survival of all patients treated with lymphodepletion was 60% at one year," she added.

Specifically, a pediatric patient with metastatic rhabdomyosarcoma, who had spread to the bone marrow, achieved a complete response (CR) for one year, but then recurred; reprocessing with CAR T cells obtained continuous CR for 17 months. Multiple badyzes of the patient's blood showed that there were antibody responses against several intracellular proteins involved in the cell cycle, cell growth, cell signaling, as well as invasion and metastasis.

In addition, the data showed that a pediatric patient with metastatic osteosarcoma, which had spread to the lungs, had continuous CR for 32 months.

In terms of safety, treatment-related toxicities were limited, Navai said. Eight patients experienced a grade 1/2 cytokine release syndrome within 24 hours after the T-CAR infusion, which was completely resolved after supportive care within 5 days of onset. As a result of chemotherapy, all patients experienced a decrease in their blood counts, which improved thereafter; no patient has developed secondary infections resulting in low blood counts and no neurological toxicity has been observed.

"Despite this improved expansion, we did not observe any dose-limiting toxicity," Navai said. "No serious cardiac or pulmonary toxicity was observed and all patients maintained normal cardiac function throughout the duration of the study and during longer-term follow-up. I note this because patients receiving other treatments directed by HER2, such as trastuzumab, are at risk of weakening cardiac function. "

Phase II trials of HER2-specific T-cells alone or in combination with other approaches in a larger number of patients are needed to determine the efficacy and optimal dosage. Navai also explained that future research would likely examine this therapeutic approach in other HER2-positive tumors beyond sarcomas.

Reference:
Navai SA, C Derenzo, Joseph S, et al. The administration of HER2-CAR T lymphocytes after lymphodéplétion safely improves the expansion of T cells and induces clinical responses in patients with advanced sarcomas. Presented at: 2019 AACR Annual Meeting; From March 29 to April 3, 2019; Atlanta, GA. Abstract LB-147.