Advances in CAR T-Cell Therapy in CCA

Chimeric antigen receptor (CAR) T cells are a novel therapy that uses CARs to combine the effector function of T cells with the ability of antibodies to recognize distinct surface antigens. The process to engineer T cells begins by harvesting a patient’s own T cells, which are then modified ex vivo with a construct encoding a CAR. The CAR T cells undergo ex vivo expansion and are reinfused back into the patient where they undergo in vivo expansion and perform their therapeutic function.¹ CD19-directed CAR T cells have shown therapeutic benefit in acute lymphocytic leukemia, B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, whereas B-cell maturation antigen–directed CAR T cells have proved effective in multiple myeloma.¹ Although some success has been achieved in hematologic cancers, many barriers still need to be overcome to translate efficacy to solid tumors. Mark O’Hara, MD, discussed the potential of CAR T-cell therapy in cholangiocarcinoma (CCA), touching on CAR T-cell target selection, the ability to traffic CAR T cells to solid tumors, and the possibility of an immunosuppressive microenvironment.¹ Optimal CAR T-cell target selection in CCA includes targets that are extracellular membrane bound and are highly expressed on tumor cells but not on normal tissue. Potential targets and the estimated expression are shown the Figure.¹

A phase 1 trial of EGFR-positive CAR T-cell therapy in CCA demonstrated a median progression-free survival of 4 months from the first cycle of treatment, and of 17 evaluable patients, 1 patient had a complete response and 10 had stable disease.² Evidence of on-target, off-tumor activity was seen, with adverse events that included mucosal/cutaneous toxicities such as oral mucositis/ulcer, gastrointestinal hemorrhage, and pruritus.² M5 CAR T cells were studied in 3 patients with pancreatic cancer in cohort 1; the best response was stable disease in 1 of 3 patients.¹ Toxicities were limiting, however, and 2 of 3 patients developed pneumonitis, both of which had pulmonary metastases.¹ To mitigate trafficking of CAR T cells, regional delivery of M5 CAR T-cell therapy was studied in 2 additional cohorts: cohort 2 using intraperitoneal infusion and cohort 3 using intrahepatic delivery (2 intravenous infusions separated by 3 weeks after regional delivery).¹ In this study, CAR T-cell therapy made it to the tumor without the same inflammatory toxicities.¹ With evidence that CAR T cells are able to get to the tumor, strategies to optimize CAR T cells are needed, which may include combination therapies to increase efficacy. Mesothelin CAR T cells combined with immune checkpoint inhibition (ICI) was studied in patients with malignant mesothelioma, and the investigators found an increase in responses, including increased CAR T-cell circulation in the blood, in patients who received both CAR T-cell therapy and ICI treatment.³

Additional research is ongoing to understand additional ways to optimize CAR T cells. Gavo-cel (TC-210) is a mesothelin-targeting T-cell receptor fusion construct (TRuC) being studied in mesothelin-expressing tumors, including CCA. TRuC T cells use an entire endogenous T-cell receptor fused with antibodies to target mesothelin in a human leukocyte antigen–independent manner.⁴ A phase 1 study led to orphan drug approval of gavo-cel for mesothelin-expressing tumors, including CCA,⁴ and a phase 1/2 expansion study is ongoing that investigates gavo-cel as monotherapy and in combination with ICI.⁵ SynKIR also uses an alternative design to increase CAR T-cell function and efficacy. The killer immunoglobulin-like receptor (KIR)-based CAR triggers antigen-specific proliferation and effector function in vitro when introduced into human T cells with DAP12, an immunoreceptor.⁶ A phase 1 trial is currently recruiting with aims to investigate mesothelin-directed SynKIR CAR T cells in mesothelin-positive CCA, ovarian cancer, and mesothelioma.¹

Sources:

1. O’Hara M. The potential of CAR T cell therapy in cholangiocarcinoma. Presented at: Cholangiocarcinoma Foundation meeting, April 12-14, 2023; Salt Lake City, UT.
2. Guo Y, Feng K, Liu Y, et al. Phase I study of chimeric antigen receptor-modified t cells in patients with EGFR-positive advanced biliary tract cancers. Clin Cancer Res. 2018;24(6):1277-1286.
3. Adusumilli PS, Zauderer MG, Rivière I, et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. 2021;11(11):2748-2763.
4. Hong DS, SciMentum SL, Tanyi J, et al. Gavocabtagene autoleucel (gavo-cel, TC-210) dose escalation in refractory mesothelin-expressing solid tumors. Ann Oncol. 2021;32(S5):S830.
5. TCR2 Therapeutics. Phase 1/2 trial of gavo-cel (TC-210) in patients with advanced mesothelin-expressing cancer. ClinicalTrials.gov identifier NCT 03907852. Updated May 8, 2023. https://clinicaltrials.gov/ct2/show/NCT03907852. Accessed May 30, 2023.
6. Wang E, Wand L-C, Tsai C-Y, et al. Generation of potent T-cell Immunotherapy for cancer using DAP12-based, multichain, chimeric immunoreceptors. Cancer Immunol Res. 2015;3(7):815-826.