Automated Manufacturing Helps Maintain Efficacy of BNT211 in Solid Tumors

BNT211, a CLDN6-directed CAR T-cell therapy, has shown encouraging signs of activity and a manageable safety profile with or without the addition of CLDN6-encoding mRNA vaccine (CARVac) in patients with CLDN6-positive relapsed/refractory advanced solid tumors, when manufactured through an automated process.¹

The findings were presented in a poster discussion during the 2023 ASCO Annual Meeting.

BNT211 was previously evaluated following manual production in a phase 1 dose-escalation study and data from 21 efficacy-evaluable patients were presented at the2022 ESMO Annual Congress.2 The dose-escalation protocol was replicated to evaluate the automated BNT211 product both as monotherapy and in combination to support scaled-up manufacturing process.1 Findings were presented by John B. A. G. Haanen, MD, PhD, of the Netherlands Cancer Institute.

In the automated process analysis, best response, as measured by change in target sum, was 41% among 17 evaluable patients treated with BNT211 with or without CARVac. The disease-control rate (DCR) was 65%.¹

Most responses were driven by patients who received BNT211 at dose-level 2 (1 × 10⁸ CAR T; n = 8); the objective response rate (ORR) in this group was 75%. Among patients who received dose-level 1 (1 × 10⁷ CAR T; n = 7) or dose-level 0 (1 × 10⁶ CAR T; n = 2), the ORR was 11%, with 1 patient having a partial response (PR). The DCR in the dose-level 2 group was 88% and was 33% in dose-level 1 or lower group.¹

In terms of safety, no dose-limiting toxicities (DLTs) were reported at any dose level and were in-line with that of the manually produced BNT211 products.1 Of note, 2 patients reported DLTs, including 1 treated at dose level 2 with BNT211 monotherapy and 1 treated at dose level 2 in combination with the CLDN6-encoding mRNA vaccine in the manual product cohort.²

Efficacy was deemed comparable by investigators to the manual product analysis, which elicited an ORR of 33%, including 1 patient with a complete response (CR) and 6 patients with a PR. Seven patients reported stable disease (SD) and the DCR was 67%.² Investigators also presented an update from the manual product cohort, which showed that 3 of the 13 patients with germ cell tumors had ongoing clinical benefit as of the March 10, 2023, data cutoff. One patient treated at dose-level 2 had an ongoing CR with BNT211 alone; 1 patient treated at dose-level 1 in combination with CARVac reported a third PR; and 1 patient treated at dose-level 2 plus CARVac had ongoing SD.

As of data cutoff of March 10, 2023, surgical complete response was reported in 1 patient with testicular cancer treated with the automated product. Five PRs were reported 4 of which were in patients with ovarian cancer and 1 with other tumor type. Further, 3 patients had SD.

In the phase 1/2a trial, escalating doses of the autologous CAR T-cell therapy BNT211 with or without CARVac were administered at 50 µg then 100 µg if tolerated. Patients with relapsed or refractory solid tumors were required to have CLDN6-positivity, defined as at least 50% of tumor cells being 2+ or 3+ (CLDN6-high). They also needed to have measurable disease or elevated tumor marker and an ECOG performance status of 0 or 1.

All patients underwent lymphodepletion prior to CAR T infusion and DLTs were assessed for 28 days. CARVac was administered at a fixed dose starting day 4 of the cycle every 3 weeks for 5 cycles, then switched to every 6 weeks. Redosing with the CAR T product was permitted. Efficacy assessments were conducted every 6 weeks using RECIST 1.1 criteria. Primary end points were safety, tolerability, and DLTs. Secondary end points included immunogenicity, ORR, DCR, and duration of response.

The second-generation, CLDN6-directed CAR T-cell product was developed in tandem with the clinically validated RNA-lipoplex vaccine for body-wide delivery of antigens to dendritic cells. Through repeat administration, the vaccine has demonstrated amplification and persistence of CAR T cells.¹

Regarding safety, 19 patients were included in the safety population. For those who received the CLDN6-directed CAR T product alone, grade 3 or higher treatment-emergent adverse effects (TEAEs) were reported in all patients treated at each dose-level, these effects were mostly associated with lymphodepletion or elevations of transaminases and bilirubin, according to investigators. Grade 3 or higher TEAEs related to the investigational product were reported among 1 patient treated at dose-level 0, 1 patient treated at dose-level 1, and 5 patients treated at dose-level 2. One treatment-emergent serious effect was sepsis reported at dose-level 0, which investigators noted that the patient went on to develop Klebsiella infection and a second grade 3 sepsis event.

For patients who received the combination of BNT211 with CARVac, grade 3 or higher TEAEs were reported in 2 patients treated at dose-level 1 and all patients treated at dose-level 2. Grade 3 or higher TEAEs related to the investigational product were reported in 1 patient who received dose-level 1 and 2 patients who received dose-level 2.

Regarding cytokine release syndrome (CRS), 5 patients experienced an event including 4 patients receiving monotherapy (dose-level 0, n = 1; dose-level 2, n = 3), and 1 patient in the combination cohort (dose-level 1). Most CRS events were grade 1/2, and 1 event was grade 3 and investigators noted was related to the CLDN6 CAR T product. Five deaths were reported across the monotherapy treatment doses, and all were because of disease progression.

Investigators concluded that follow-up will continue and active recruitment for dose-level 2 and dose-level 3 (2 to 5 × 108 CAR T) is ongoing. Once a recommended phase 2 dose is determined a pivotal trial in germ cell tumors will be initiated with a priority medicines designation from the European Medicines Agency.

_REFERENCES:

_{1. Mackensen A, Haanen JBAG, Koenecke C, et al. CLDN6 CAR-T cell therapy of relapsed/refractory solid tumors ± a CLDN6-encoding mRNA vaccine: dose escalation data from the BNT211-01 phase 1 trial using an automated product. J Clin Oncol. 2023;41(suppl 16):2518. doi:10.1200/JCO.2023.41.16_suppl.2518}

_{2. Mackensen A, Haanen JBAG, Koenecke C, et al. BNT211-01: a phase I trial to evaluate safety and efficacy of CLDN6 CAR T cells and CLDN6-encoding mRNA vaccine-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumours. Ann Oncol. 2022;33(suppl 7):S1404-1405. doi:10.1016/j.annonc.2022.08.035}