CAR-T with, without mRNA vaccine shows promise for solid tumors
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Early data from a phase 1 trial showed encouraging clinical activity for an investigational chimeric antigen receptor T-cell therapy alone or in combination with an amplifying mRNA vaccine for patients with solid tumors.
Forty-three percent of patients treated during the study achieved an objective response, according to results presented at American Association for Cancer Research Annual Meeting.
Background
The investigational treatments used in the trial included BNT211 (BioNTech) — an autologous CAR-T cell therapy that targets the oncofetal antigen Claudin-6 (CLDN6) — and CARVac (BioNTech), a CLDN6-encoding mRNA-based vaccine designed to enhance CAR T-cell activity.
CLDN6 is an attractive target for CAR T-cell therapy because it is absent in adult healthy tissue but is highly expressed in certain cancers, John Haanen, MD, PhD, professor of translational cancer immunotherapy at Leiden University Medical Center and leader of the cancer immunotherapy research group at Netherlands Cancer Institute, said during a presentation. This is especially true for testicular and ovarian cancers, both of which have been shown to have high expression of the antigen, he added.
“CARVac was developed to target antigen-presenting cells in lymphoid tissue after systemic administration,” Haanen said. “[It] drives the expansion and persistence of CAR T cells while enhancing their antitumor activity.”
Methodology
Haanen and colleagues enrolled 16 patients (median age, 46 years; range, 23-68; 62.5% male) as part of a phase 1/phase 2 multicenter dose-escalation study to evaluate the safety and efficacy of BNT211 alone or in combination with CARVac for patients with relapsed or refractory CLDN6-positive solid tumors.
The bifurcated first-in-human trial includes dose-escalation portions for BNT211 as monotherapy or in combination with CARVac. All study participants underwent lymphodepletion prior to infusion with BNT211 regardless of the treatment arm.
Study participants received a median four (range, two to 11) lines of prior therapy.
The efficacy analysis included 14 patients who received follow-up assessments 6 months after CAR T-cell infusion as of the data cutoff date of March 10, 2022.
Median follow-up was 127 days (range, 2-348).
Key findings
Two patients experienced dose-limiting toxicities. This included one patient each at dose level two in the monotherapy and combination therapy treatment groups. Grade 3 or higher treatment-related adverse events more than doubled in dose level two for both treatment arms.
Seventy percent of patients experienced grade 1 or grade 2 cytokine release syndrome. No patients experienced neurotoxicity during the study.
The investigators noted pronounced cytopenia among patients with testicular cancer who recently received high-dose chemotherapy and autologous hematopoietic stem cell transplant. This prompted the researchers to open a new study cohort for these patients that used a reduced lymphodepletion regimen prior to CAR T-cell infusion. This group had an ORR of 80%, with a disease control rate of 100%. One in the cohort had a complete response to therapy.
Efficacy analysis showed an ORR of 43% and disease control rate of 86% among patients who received an initial 6-month follow-up evaluation.
The combination therapy groups had higher ORRs compared with monotherapy. No patients who received CAR T cells alone at dose level one achieved a response to therapy vs. 33% in the combination arm. Likewise, 33% of patients had a response at dose level two of CAR T cells alone compared with 75% who received both CAR T-cells and CARVac.
Clinical implications
Patients tolerated CLDN6-directed CAR T cells well at all dose levels evaluated and had manageable treatment-related adverse events, Haanen said.
“We found robust engraftment of CAR T cells in all patients,” he said during a presentation. “This translated into a very encouraging clinical benefit.”
The five patients with testicular cancer in the reduced lymphodepletion cohort had the most encouraging results, Haanen said.
“Combining a CAR and mRNA-mediated antigen delivery is a promising approach to rescue CARs that may not encounter enough tumor cells or engage enough antigen on tumor cells to be effective,” Michel Sadelain, MD, PhD, director of Center for Cell Engineering at Memorial Sloan Kettering Cancer Center and member of the Healio | Cell Therapy Next Peer Perspective Board, told Healio.
“The mechanism of action of CARVac, depending on what cell types express the targeted antigen, will be important to determine to maximize efficacy and minimize toxicity,” added Sadelain, who was not involved with the study.
Perspective
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Henry Chi Hang Fung, MD, FACP, FRCPE
CAR T-cell therapy has become the standard of care for selected patients with lymphomas, multiple myeloma and acute lymphoblastic leukemia but not for any solid tumors. Results from previous studies of solid tumors have been disappointing. Here, a CAR T-cell product targeting CLDN6 is novel and has demonstrated promising results in selected solid tumors. The combination of an mRNA vaccine with CAR-T is a novel approach, although the impact on outcomes remains unclear. Hopefully, CAR T-cell therapy will soon become a treatment option for patients with solid tumors and address unmet needs for our patients.
Perspective
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Vincent K. Lam, MD
CAR-T progress in solid tumors has been hampered by several key challenges, including difficulty in identifying a safe and effective target, tumor heterogeneity, and maintaining an adequate T-cell response in the setting of a hostile tumor microenvironment. This study brings together two key innovations that address some of these challenges — namely, the identification of CLDN6 as a novel CAR-T target, as well as the use of an mRNA vaccine to enhance CAR-T persistence.
Results from this study are an exciting and important advance for a rapidly growing field. For the first time, CLDN6 has been clinically validated as a novel CAR-T target, with promising clinical activity in testicular and ovarian cancer.
CARVac appears safe in combination with CLDN6-directed CAR-T, but CAR-T persistence does not appear to be consistently enhanced yet. Open questions include: What is the optimal dose, timing and duration of CARVac? Could the vaccine-boosting effect be even more apparent in a tumor with lower antigen density? What is the contribution, if any, of endogenous CLDN6-specific T cells to the clinical responses observed in this study? And how might we best use immune checkpoint blockade in this combined setting?
I eagerly await the results of further correlative studies — in particular, on-treatment biopsies that may be able to demonstrate CAR-T interaction with the tumor microenvironment and potential mechanisms of resistance.
Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy
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Haanen J, et al. Abstract CT002. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
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