ADP-A2AFP SPEAR T Cells Demonstrate Efficacy, Tolerability in Advanced HCC

Bruno Sangro, MD, PhD

ADP-A2AFP specific peptide enhanced affinity receptor (SPEAR) T cells were associated with an acceptable safety profile and elicited antitumor activity in patients with advanced hepatocellular carcinoma (HCC), according to data from the third-dose cohort and expansion phase of a phase 1 trial (NCT03132792) that was presented during the 2021 International Liver Cancer Association Conference.¹

At the data cutoff date of April 15, 2021, results showed that the disease control rate in the 13-patient cohort was 64% and 1 patient experienced a complete response (CR). A total of 6 patients experienced stable disease (SD), 4 had SD less than 16 weeks’ duration, and 2 had SD of at least 16 weeks’ duration. Four patients experienced progressive disease (PD) and 2 patients were not evaluated because they had not had first scans at the time of the cutoff date.

“SPEAR T cells are autologous T cells that are engineered in vitro to express a T-cell receptor (TCR) that recognizes with high-affinity peptides from [α-fetoprotein],” explained lead study author Bruno Sangro, MD, PhD, director of the Liver Unit and co-director of the HPB Oncology Area at Clinica Universidad de Navarra in Pamplona, Spain.

“Based on this principle, this phase 1, first-in-human trial in patients with advanced HCC is testing if patients are compatible for the treatment, based on HLA compatibility and α-fetoprotein expression. If they are eligible, patients are provided an infusion of SPEAR T cells after a lymphodepleting regimen, with safety and efficacy monitoring coming afterwards.”

Sangro noted that SPEAR T cells have access to a broader spectrum of intracellular and extracellular proteins, giving them the ability to target solid tumors.

After the lymphodepletion phase on days -7 to -5/-4 of the trial, patients were given a SPEAR T-cell infusion on day 1, followed by hospitalization until day 7. Post-infusion assessments included safety monitoring, cytokine monitoring, and T-cell persistence. Patients stayed on the trial until disease progression, death, or early study withdrawal.

Key eligibility criteria included histologically confirmed HCC not amenable to locoregional therapy with an ECOG performance score of 0 to 1. Eligible patients were those with progressive disease on, intolerance to, or refusing standard systemic therapy. Patients also needed to have a Child-Pugh score of 6 or less without ascites or encephalopathy and an HLA-A*02:01 and evidence of tumor α-fetoprotein expression, defined by tumor immunohistochemistry analysis or serum α-fetoprotein greater than 100 ng/mL.

The cohort’s transduced cell dose was approximately 5 x 10⁹ (1.2x 109-6 x 10⁹). The median transduced cell dose was 5.11 x 10⁹ (range, 5.05 x 10⁹ to 5.64 x 10⁹) in 3 patients and 7.34 x 10⁹ (range, 4.42 x 10⁹ to 9.98 x 10⁹) in 10 patients. Both dose levels were given a lymphodepleting chemotherapy regimen of cyclophosphamide 600 mg/m² daily for 3 days and fluorouracil 30 mg/m² daily for 4 days.

In the overall cohort, the median age of the population was 60 (range, 32-75) and 77% were males. Patients had a median of 2 (range, 1-4) prior lines of systemic therapy and 4 patients had undergone prior liver cancer surgery. Common prior liver diseases included cirrhosis (n = 6), hepatitis B (n = 3), and hepatitis C (n = 5). The majority of patients (n = 8) were Barcelona- Clinic Liver Cancer stage C at screening.

The most common adverse events (AEs) of any grade were neutropenia (54%), leukopenia, lymphopenia, and pyrexia (38% each). AEs of at least grade 3 included neutropenia (46%), leukopenia (38%), lymphopenia (31%), and febrile neutropenia (23%).

Serious AEs occurred in 4 patients, 2 of which were related to T-cell infusion. Febrile neutropenia, infusion-related reaction, cytokine release syndrome, back pain, and bile duct obstruction were observed in 1 patient each. There were no grade 4/5 serious AEs.

Most of the AEs were consistent with cytotoxic chemotherapy, cancer immunotherapy, and/or cell therapy. Hepatobiliary AEs were most consistent with HCC or underlying disease and no clear evidence of ADP-A2AFP–induced hepatoxicity was reported.

Investigators found that higher SPEAR T-cell doses were associated with a decrease in serum α-fetoprotein levels. They also noted that clinical benefit is associated with sustained reduction in serum α-fetoprotein levels.

A positive correlation (r = 0.82; P > .0001) was observed between peak persistence and dose. Patients receiving the highest doses also had the most obvious persistence. SPEAR T-cell infiltration was seen in all available post-infusion tumor biopsies and was found to be higher in patients with SD.

“SPEAR T cells up to doses of 10 billion transduced cells have been associated with an acceptable safety profile,” concluded Sangro. “One patient had a sustained CR with normalization in serum α-fetoprotein, indicating as a proof-of-concept that this form of cell therapy can be active in the setting of advanced HCC. ADP-A2AFP SPEAR T-cells persisted in the periphery in a dose-dependent manner and were detected in post-infusion tumor tissue.”

_REFERENCES:

_{Sangro B, Meyer T, Mahipal A, et al. Data from the third dose cohort and expansion phase of a phase 1 trial of ADP-A2AFP SPEAR T-cells for patients with hepatocellular carcinoma and other cancer types expressing alpha-fetoprotein. Presented at: 2021 International Liver Cancer Association Conference. September 2-5, 2021. virtual. https://bit.ly/3k7ileU}