CAR T Cell’s Promise: “[A] single infusion may... keep that cancer in remission.”

The benefits observed from chimeric antigen receptor (CAR) T-cell therapy, especially in patients with B-cell leukemia and lymphoma, have demonstrated its anticancer potential. Overall, 6 CAR T-cell therapies have gained FDA approval across hematologic malignancy settings (TABLE).¹ These approvals have spurred further exploration for their use in solid tumors. Two factors have fueled investigators’ continuing efforts. First, CAR T-cell therapy holds the promise of being a singular therapy.

“Traditional treatments, whether chemotherapy, antibody-drug conjugates, hormonal therapies, [or] others, all require continuous ongoing cycles in which the patient returns for further treatment,” Oladapo Yeku, MD, PhD, said in an interview with . “For CAR therapy, a single infusion may be all that’s needed to keep that cancer in remission,” Yeku said. Yeku is an assistant professor at Harvard Medical School and director of translational research in the Gynecologic Oncology Program at Massachusetts General Hospital in Boston.

Second, from a biological point of view, CAR T cells are living drugs, unlike traditional treatments, and can foster the creation of memory cells. These cells can help A cells persist longer, exhibit greater antitumor activity, and expand when malignancy is encountered, Yeku said.²

Another encouraging sign is medicine’s greater understanding of the immune system and its relationship to the tumor microenvironment. Preclinical and clinical efforts have turned to identifying potential target antigens. Several target antigens have been identified in solid tumors, with some demonstrating safety and feasibility in preclinical and clinical trials. Although a handful of these early trials have been completed, the potential for clinical use remains elusive.

A recent study published in the evaluated CAR T cells that targeted disialoganglioside GD2 expressed on tumor cells.³ In the phase 1/2 trial (NCT03373097), 27 children with neuroblastoma who were heavily pretreated received the CAR agent.

In the phase 1 portion of the trial, 3 CAR T-cell dose levels were evaluated: 3 × 10⁶, 6 × 10⁶, and 10 × 10⁶ CAR T cells/kg. In phase 2, the recommended dose was determined to be 10 × 10⁶ CAR-positive T cells/kg.

Seventeen patients had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 patients had a partial response. Among the patients who received the recommended dose, the 3-year overall and event-free survival were 60% and 36%, respectively.³

Regarding safety, investigators reported 20 cases of cytokine release syndrome (74%) with 95% of the cases determined to be mild. In 1 patient, a suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to months after infusion median persistence, 3 months; range, 1-30).³

Brain Cancer

Brain malignancies, such as glioblastoma multiforme, are also undergoing evaluation, according to Analiz Rodriguez, MD, PhD.

“The challenge with glioblastoma is that it is extremely heterogeneous,” Rodriguez told Targeted Therapies in Oncology. “Not every cancer cell in that tumor may express that antigen. Going further, although targeting 1 antigen may elicit a response, if the cancer recurs the tumor may no longer express that antigen because it has figured out how to bypass the treatment.” A number of trials have evaluated IL13Ra2, HER2, and EGFR, Rodriguez added.

A phase 1 trial (NCT00730613) determined the adverse events associated with the infusion of CAR T-cells in patients with recurrent or refractory high-grade malignant glioma.⁴ The primary end point was to assess the feasibility and safety of A -cell therapy that was modified to express the IL-13 zetakine chimeric immunoreceptor and the Hy/TK selection/suicide fusion protein in patients with recurrent or refractory, high-grade malignant glioma. Secondary end points included evaluating the antitumor activity of adoptively transferred clones in these patients and screening for the development of anti-IL13 zetakine immune responses in these patients.

Another phase 1 dose escalation study (NCT01109095)5 evaluated a total of 17 patients (9 males) with progressive HER2-positive glioblastoma. Patients had received 1 or more infusions of autologous HER2-CAR virus-specific cells (VSTs; 1 × 10⁶/m2 to 1 × 10⁸/m²) without prior lymphodepletion. Ten patients were 18 years or older and 7 patients were younger than 18 years.

Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and antiglioblastoma activity.

Researchers noted that the treatments were well tolerated; no dose-limiting toxicities were observed.

Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease (range, 8 weeks to 29 months), and 8 progressed after T-cell infusion.⁵

Completed Trials in Other Solid Tumors

Other completed trials include one by Haas et al, which evaluated the safety and activity of lentiviral-transduced CAR- modified autologous T cells redirected against mesothelin (meso) in patients with malignant pleural mesothelioma, ovarian cancer, and pancreatic ductal adenocarcinoma (NCT02159716).⁶ Nineteen patients were determined to be eligible and underwent leukapheresis. Four treatment cohorts were identified and received CAR T-meso cells on day 0 with or without cyclophosphamide. Tumors were assessed using CT scans of the chest, abdomen, and pelvis at baseline and 1, 3, and 6 months after CAR T-meso infusion.⁶

The best overall response based on RECIST v1.1 criteria (for pancreatic ductal adenocarcinoma and ovarian carcinoma) and on modified criteria for malignant pleural mesothelioma) was stable disease observed in 11 of 15 patients at 28 days and in 3 of 8 patients on follow-up at months 2 and 3, respectively.⁶ A dose-limiting toxicity was defined as grade 3 or higher hematologic or nonhematologic toxicity that developed after dosing through day of the safety follow-up visit and was new not e istent before infusion and at least possibly related to cells. Researchers reported that CAR T-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.

Another trial (NCT02416466) evaluated patients with carcinoembryonic antigen (CEA)-positive and liver metastases (LMs) who received anti-CEA CAR T-cell hepatic arterial infusions As and selective internal radiation therapy . The primary end point for the phase 1b HITM-SIR trial was safety with secondary assessments of biological activity. Enrolled patients had a mean LM size of 6.4 cm, 4 patients had fewer than 10 LMs, and patients received an average of 2 lines of prior systemic therapy.

No grade or toxicities were observed, and there were no instances of severe cytokine release syndrome or neurotoxicity. Median survival time was 8 months (mean, 11; rand, 4-31) Anti-CEA CAR T-cell HAI with subsequent SIRT was well tolerated, and biological responses were demonstrated following failure of conventional therapy.⁷

Ovarian Cancer

Some of the common cell surface antigens (mesothelin, Muc16, HER2, and folate receptors) that are overexpressed on ovarian cancer cells are undergoing investigation in CAR T-cell development. Muc16 (CA125) CAR T cells, modified to secrete IL-12, were tested in a phase trial using intravenous and intraperitoneal administration with “stable disease” as the best observed clinical response in a cohort of heavily pretreated patients with epithelial ovarian cancer.⁹

A number of trials are actively recruiting patients with ovarian cancer. For example, a single-center, double-arm, open-label study (NCT06215950)¹⁰ is evaluating the safety and efficacy of CD70-targeting A cells in the treatment of CD70-positive advanced metastatic gynecologic cancer. researchers are obtaining recommended doses and infusion patterns.

The 2-arm study will have an intravenous infusion group and an intraperitoneal injection group with phases. Phase will be the dose discovery phase used to determine recommended doses. The second phase will be a dose expansion phase to verify the safety of the recommended doses. Investigators plan to enroll 12 patients.

Another actively recruiting phase 1 trial (NCT05225363) is testing the safety, adverse effects, and best dose of TAG72 CAR T cells in treating patients with epithelial ovarian cancer that remains despite treatment with platinum therapy (platinum resistant).

The primary end points are safety and tolerability of TAG-72 CAR T cells, determining the maximum tolerated dose, and identifying the recommended phase dose. Secondary end points include persistence of CAR T cells in the blood, response, median overall survival, and determination of the TAG-72 expression on tumor cells by immunohistochemistry.¹¹

Exploratory objectives include determining the phenotype and frequencies of immune cell subsets in the peripheral blood (pre- and post therapy), determining the phenotype of tumor-infiltrating lymphocytes, and gene expression of circulating tumor cells.¹¹

Challenges and Barriers

Yeku pointed out the challenges and barriers associated with the use of CAR T-cell therapy.

Impaired CAR T-cell proliferation and persistence, an immunosuppressive tumor microenvironment, limited CAR T-cell access to the tumor trafficking, and exhaustion of the CAR T-cell function are proven obstacles to overcome.¹²

Inherent in treating solid tumors is the heterogeneous nature of the tumor. Developing a CAR T-cell therapy that works in gastric cancer may have no effect on ovarian cancer, even though they might both express the same target. In blood cancers, many targets are well established. or example, CD19 and BCMA in B-cell lymphoma and multiple myeloma, respectively, are very well-established targets that are expressed in the majority of these tumors. Solid tumors, on the other hand, have a limited number
of targets, and these targets could also be expressed in healthy, normal tissue.

Giving CAR T cells that target HER2, which could be expressed in the tumor as well as the heart, can end up being detrimental, Yeku said. “Some early CAR studies were closed because of these adverse events. Some targets were expressed in the liver and other places that we didn’t appreciate, leading to dramatic toxicities,” Yeku said. “The targets we have in solid tumors and their in situ behavior are more nuanced than what we see in hematologic malignancies.”

There are also barriers to using CAR T-cell therapy. Manufacturing and timing logistics, quality assurance testing, and social determinants can affect access to care. “These therapies can only be delivered at accredited academic facilities,” Yeku noted. “But patients who live in rural communities, or those with limited financial resources, will have limited access, even when CAR T-cell treatments are approved by the FDA.

Balancing Act

As with all approaches, there is a risk-benefit ratio that must be weighed and discussed with patients, Yeku said. “Because of what we’ve learned about the adverse events associated with CAR T-cell therapy in hematologic malignancies, we have been able to manage serious toxicities, such as cytokine release syndrome,” Yeku said. As the experience with using CAR T-cell therapy grows, Yeku expects investigators and clinicians will be better able to address these adverse events. He said the researchers whose results were published in the New England Journal of
Medicine study³ used a “suicide switch” to turn off the CAR T-cell when it was determined that the toxicities became too great.

“Although we’re designing more potent and efficacious CAR T-cell agents, we also need to work on minimizing acute and long-term toxicity,” Yeku said, noting the increased awareness of the risk of secondary cancers that have been reported in a small number of patients.^13,14

Nonetheless, Yeku is hopeful about the future of CAR T-cell therapy. “There are many different ways we can approach this therapy, and there are many researchers who are exploring proof of principle and preclinical studies as we speak,” he concluded.

REFERENCES
1. Food and Drug Administration. Approved cellular and gene therapy products. Accessed February 5, 2024. https://tinyurl.com/5n7d6zj2
2. López-Cantillo G, Urueña C, Camacho BA, Ramírez-Segura C. CAR-T Cell Performance: How to Improve Their Persistence?. Front Immunol.2022;13:878209. Published 2022 Apr 28. doi:10.3389/fimmu.2022.878209
3. Del Bufalo F, DeAngelis B, Caruana I, et al. GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma. N Engl J Med. 2023; 388:1284-1295. doi:10.1056/NEJMoa2210859
4. Cellular Adoptive Immunotherapy Using Genetically Modified T-Lymphocytes in Treating Patients With Recurrent or Refractory High-Grade Malignant Glioma. ClinicalTrials.gov. Accessed February 9, 2024. https://clinicaltrials.gov/study/NCT00730613
5. Ahmed N, Brawley V, Hegde M, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncol. 2017;3(8):1094-1101. doi:10.1001/jamaoncol.2017.0184
6. Haas AR, Tanyi JL, O’Hara MH, et al. Phase I study of lentiviral transduced chimeric antigen receptor-modified t cells recognizing mesothelin in advanced solid cancers. Mol Ther.2019;27(11):1919-1929. doi:10.1016/j.ymthe.2019.07.015
7. Katz SC, Hardaway J, Prince E, et al. HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+liver metastases. Cancer Gene Ther. 2020;27(5):341-355. doi:10.1038/s41417-019-0104-z
8. Sarivalasis A, Morotti M, Mulvey A, Imbimbo M, Coukos G. Cell therapies in ovarian cancer. Ther Adv Med Oncol. 2021;13:17588359211008399.
doi:10.1177/17588359211008399
9. Koneru M, O’Cearbhaill R, Pendharkar S, Spriggs DR, Brentjens RJ. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med. 2015;13:102. Published 2015 Mar 28. doi:10.1186/s12967-
015-0460-x
10. A Phase I Clinical Study to Assess the Safety and Efficacy of CD70-targeted CAR-T in the Treatment of CD70-positive Advanced/Metastatic Gynecologic Cancer. Clinicaltrials.gov. http://tinyurl.com/3ebv52ek. Accessed February 10, 2024.
11. A Phase 1 Study to Evaluate TAG72-Targeting Chimeric Antigen Receptor (CAR) T Cells in Patients With Advanced Epithelial Ovarian Cancer. Clinicaltrials.gov. Accessed February 10, 2024. http://tinyurl.com/3rn6pvyr.
12. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020;17(3):147-167. doi:10.1038/s41571-019-0297-y
13. Serani S. FDA Initiates Investigation of CAR T Immunotherapies. Targeted Therapies in Oncology. Accessed February 10, 2024. http://tinyurl.com/mmcf4atr.
14. FDA Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies. FDA. Accessed February 10, 2024. http://tinyurl.com/4cx52j8p.