Targeted CAR T-Cell Therapies Show Early Efficacy in Solid Tumors With Focus on Mitigating Toxicity

Renier Brentjens, MD, PhD

Several targeted chimeric antigen receptor (CAR) T-cell therapies are beginning to show early signals of efficacy for patients with solid tumors as investigators are working to translate the efficacy and safety profiles seen with these agents in hematologic malignancies to the solid tumor field. Among them are satricabtagene autoleucel (satri-cel; CT041),1,2 autologous GD2-CART,3 ALLO-316,4 GCC19CART,5 and more, according to recent data. The FDA has also granted fast track designation and regenerative medicine advanced therapy (RMAT) designation to several of these agents as they undergo further examination in early-phase trials.2,4,5

“When you move from blood cancers to solid tumor cancers, the structure of the tumor is a lot different. The first thing is that there is a massive amount of target antigen heterogeneity,” Renier Brentjens, MD, PhD, said in an interview with OncologyLive. “There are 3 basic issues that are different between liquid and solid tumors: target antigen heterogeneity, an immunosuppressive microenvironment, and a fibrotic structure that makes it difficult for the CAR T cells to get into the tumor. Although the first CAR T-cell therapy was approved for pediatric acute lymphoblastic leukemia back in 2017, there haven’t been any FDA-approved CAR T-cell therapies for solid tumors because if you apply that paradigm that we did for blood cancers to solid tumors, it’s going to fail for those 3 reasons.”

Despite these challenges that must still be addressed, Brentjens remains positive. “Do I think CAR T cells will have a role in solid tumors in the next 5 to 10 years? I absolutely do,” he said. “The concept isn’t flawed; we’re just not there with the technology [yet].”

CLDN18.2-Targeryed Satri-Cel Generates Activity in GI Cancer

Final results of the single-arm, open-label, phase 1 CT041-CG4006 trial (NCT03874897) published in Nature Medicine revealed that the claudin18.2 (CLDN18.2)–directed autologous CAR T-cell therapy satri-cel was well tolerated and efficacious in patients with CLDN18.2-positive advanced gastrointestinal (GI) cancer.1 No dose-limiting toxicities (DLTs) or treatment-related deaths were reported, and the overall response rate (ORR) was 38.8% in patients treated with satri-cel (n = 98). Additionally, the disease control rate was 91.8%, the median progression-free survival (PFS) was 4.4 months (95% CI, 3.7-6.6), and the median overall survival (OS) was 8.8 months (95% CI, 7.1-10.2).

The pivotal phase 1/2 CT041-ST-01 trial (NCT04581473) examining satri-cel is underway, and the agent’s manufacturer, CARsgen Therapeutics, has announced that the study met its primary end point: There was a statistically significant improvement in PFS with satri-cel vs treatment of physician’s choice in patients with CLDN18.2-positive, advanced gastric/gastroesophageal junction cancers who experienced disease progression on at least 2 prior lines of therapy.2 The agent previously received RMAT designation from the FDA in 2022.

“Sometimes we find reassurance if the target we’re going after [has] already been [examined in] a clinical trial with a bispecific [antibody]—if it’s well tolerated there, then you’re more confident that the CAR T cell will be well tolerated,” Brentjens noted. “Clinical trials need to be designed [where] you start at very low doses of T cells so that if there is unforeseen on-target, off-tumor toxicity, you can treat [the patients] with steroids and chemotherapies to abrogate that response.”

CAR T-Cell Therapy Also Shows Early Efficacy Signals in Brain Tumors

Among patients with H3K27M-mutated diffuse midline gliomas (n = 11) who received CAR-modified T cells targeting GD2 in arm A of a phase 1 trial (NCT04196413), major volumetric tumor reductions occurred in 4 patients, and 3 patients had smaller reductions.3 Findings also showed that 1 patient had a complete response (CR) that was ongoing for more than 30 months following enrollment. In the study, patients received 1 intravenous (IV) dose of autologous GD2-CART at 2 dose levels following lymphodepleting chemotherapy, and those with benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions. No DLTs were observed at the first dose level, but 3 patients experienced dose-limiting cytokine release syndrome (CRS) at dose level 2.

“I believe we were the first to recognize CRS, and there are algorithms already in place for how to limit that toxicity,” Brentjens said. “The on-target, off-tumor toxicity is always a bit more worrisome because as much as we think that the targets we go after are safe targets, there aren’t a lot of CD19-type targets out there. You always run the risk, with maybe a handful of exceptions, that the protein that you’re going after isn’t only expressed on the tumor but is expressed on normal tissues elsewhere.”

Because 9 patients who received ICV infusions in the phase 1 trial did not experience DLTs, investigators have initiated arms B and C to test ICV-only administration with and without lymphodepleting chemotherapy. Dose level 1 was also established as the maximum tolerated IV dose.

Furthermore, Memorial Sloan Kettering Cancer Center (MSK) investigators noted that a patient with mesothelioma who first received CAR T-cell therapy following chemotherapy in a clinical trial during the fall of 2019 and then went on to receive pembrolizumab (Keytruda), is doing well as of September 2024.6 Results of a phase 1/2 study (NCT02414269) out of MSK showed that patients with malignant pleural mesothelioma (n = 18) who received a mesothelin-targeted CAR T-cell therapy plus pembrolizumab experienced a 1-year OS rate of 83%.7 Two patients achieved a complete metabolic response on PET scan, and 8 patients sustained stable disease (SD) for at least 6 months.

Brentjens noted that "combining CAR T cells with immune checkpoint inhibition [may be a way] to overcome limitations” with CAR T-cell therapy’s application in solid tumors. "It’s going to be a combination of technologies and a combination of immune-based therapies [that push the field forward],” he said.

Allogeneic CD70-Directed Agent Represents a Targeted CAR T-Cell Therapy of Promise

“Nowadays, with protein maps and RNA encyclopedias, you can find potential targets on virtually any cancer cell,” Brentjens said. “Given that they now have phage display libraries, which didn’t exist when we started, finding binders to any target that you want is much easier and can be done more rapidly. If you would have asked me 20 years ago if there is a favorable solid tumor, [I would’ve said] if you had access to an antibody that binds CEA or EGFR, then those would be the favorable ones to go after. Because the tumor microenvironment is different from tumor type to tumor type, we don’t quite yet know which armoring approach or which combination approach would be more favorable for one type of tumor vs another.”

Another promising agent appears to be ALLO316, an allogeneic CD70-directed CAR T-cell therapy, which yielded a 38% best ORR in patients with advanced renal cell carcinoma (RCC) who received dose level 2 (DL2; 80 × 106 of CAR+ cells) of the agent following fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 (n = 8) in the phase 1 TRAVERSE trial (NCT04696731).8,9 The confirmed ORR in this patient population was 25%, and all responses were in those with a high tumor proportion score of at least 50. Comparatively, confirmed ORRs were 22% among those who received fludarabine and cyclophosphamide alone (n = 18); 13% among those treated with fludarabine, cyclophosphamide, and ALLO-647, an anti-CD52 antibody (n = 8); and no responses occurred among the 8 patients who had CD70-negative disease or unknown status.8

Additionally, 2 DLTs occurred in the study which included autoimmune hepatitis and cardiogenic shock.4 Related grade 5 adverse effects (AEs) were cardiogenic shock, sepsis, and failure to thrive. The grade 3 or higher AEs that occurred in the DL2 group (n = 11) were neutropenia (64%), anemia (46%), thrombocytopenia (27%), and infection (18%). Further data from the phase 1b expansion cohort is expected to be reported midway through 2025.

As a result of the positive data from the trial in patients with RCC, the FDA granted ALLO-316 RMAT designation in October 2024 for patients with advanced or metastatic RCC; the agent previously received fast track designation in March 2023. Allogene Therapeutics, the drug’s developer, noted that ALLO-316’s unique features are cell expansion and persistence driven by CD70 CAR-intrinsic Dagger technology and tumor infiltration by CAR T cells.4

GCC19CART Produces Objective Clinical Activity in Refractory CRC

Further efficacy was seen in patients with solid tumors treated with CAR T-cell therapy, as those with metastatic colorectal cancer (CRC) who received DL2 (2 × 106 cells/kg) of GCC19CART (n = 5), the guanylate cyclase-C–targeted CAR T-cell therapy, experienced an ORR of 80%. Updated data as of December 26, 2024, revealed that this encompassed 1 pathological CR and 3 confirmed partial responses (PRs), including 1 patient who had a complete metabolic response on PET/CT.10 Those treated with dose level 1 (DL1; 1 × 106 cells/kg; n = 4) had an ORR of 25.0%; 1 patient experienced a PR, and 2 patients had a partial metabolic response on PET/CT with SD. Additionally, the median PFS was 5.0 months at a median follow-up of 16.6 months in the DL1 group and 7.8 months with a median follow-up of 7.4 months in the DL2 group.

Regarding safety, 1 patient experienced a DLT at DL2 and presented with grade 3 diarrhea, grade 4 enterocolitis, and grade 5 sepsis. Study investigators noted that preliminary results show the AE profile of GCC19CART is in line with what has been observed with other CAR T-cell therapies and that the agent showed significant antitumor activity in patients with refractory metastatic CRC.

Furthermore, investigators highlighted that GCC19CART is the first CAR T-cell therapy to their knowledge that has produced objective clinical activity in patients with refractory cancer.11 The agent previously received fast track status from the FDA in April 2022 for the treatment of this patient population.5

Regarding next steps in the field, Brentjens said, “What needs to happen at some point is [the examination of] armored CAR T cells. Armored CARs are CAR T cells that can recognize a target on the tumor but are additionally engineered to, for example, secrete proinflammatory cytokines. What happens then is that when the CAR T cell gets into the tumor, it secretes this proinflammatory cytokine that overcomes a lot of that immune suppression and engages the patient’s immune system to recognize the cancer [similar to the] way that immune checkpoint inhibitors can overcome immune suppression.”

References

1. Qi C, Liu C, Gong J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. Nat Med. 2024;30(8):2224-2234. doi:10.1038/s41591-024-03037-z
2. CARsgen announces positive topline results from China GC/GEJ pivotal phase II clinical trial of claudin18.2 CAR-T (satri-cel). News release. CARsgen Therapeutics. December 30, 2024. Accessed March 7, 2025. bit.ly/4bwD3Od
3. Monje M, Mahdi J, Majzner R, et al. Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas. Nature. 2025;637(8046):708-715. doi:10.1038/s41586-024-08171-9
4. Allogene Therapeutics announces positive phase 1 data demonstrating the potential of ALLO-316 in heavily pretreated patients with advanced renal cell carcinoma at SITC and IKCS. News release. Allogene Therapeutics. November 7, 2024. Accessed March 7, 2025. bit.ly/3FcauK4
5. Innovative Cellular Therapeutics (ICT) receives FDA fast track designation for GCC19CART, its lead solid tumor candidate, in the treatment of patients with relapsed or refractory metastatic colorectal cancer. News release. Innovative Cellular Therapeutics. April 19, 2022. Accessed March 7, 2025. bit.ly/4iq0sDa
6. Stallard J. How MSK is teaching CAR T cells to attack solid tumors. Memorial Sloan Kettering Cancer Center. September 3, 2024. Accessed March 7, 2025. bit.ly/3F809il
7. 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. doi:10.1158/2159-8290.CD-21-0407
8. Redefining the Future of CAR T: Doing What No CAR T Has Done Before. Allogene Corporate Overview. March 2025. Accessed March 7, 2025. bit.ly/3F8cAul
9. Srour SA, Chahoud J, Drakaki A, et al. ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC): updated safety and efficacy from the phase 1 TRAVERSE multicenter study. J Immunother Cancer. 2024;12(suppl 2). doi:10.1136/jitc-2024-SITC2024.0322
10. Keenan BP, Lieu CH, Fakih M, et al. A phase 1 dose-escalation study of GCC19CART: a novel CAR T-cell therapy for metastatic colorectal cancer in the United States. J Clin Oncol. 2025;43(suppl 4):175. doi:10.1200/JCO.2025.43.4_suppl.175
11. Chen N, Pu C, Zhao L, et al. Chimeric antigen receptor T cells targeting CD19 and GCC in metastatic colorectal cancer: a nonrandomized clinical trial. JAMA Oncol. 2024;10(11):1532-1536. doi:10.1001/jamaoncol.2024.3891