MAGEA4 Opens the Door for Engineered Cellular Therapies in Solid Tumors

Brian A. Van Tine, MD, PhD

With the groundbreaking FDA approval in August 2024 of afamitresgene autoleucel (afami-cel; Tecelra) for unresectable or metastatic synovial sarcoma, marking the first US approval of an engineered cell therapy for a solid tumor, investigators are turning their attention to a new therapeutic target of interest: melanoma-associated antigen 4 (MAGEA4), the antigen that afami-cel targets.¹

“MAGEA4 is a protein that gets reexpressed on certain cancer cells as part of the transcriptional reprogramming that happens when a cancer revolves from a normal cell state into a cancer cell state,” Brian A. Van Tine, MD, PhD, the sarcoma program director and a professor of medicine in the Division of Medical Oncology and a professor of pediatrics at Washington University in St Louis, Missouri, explained in an interview with OncologyLive. “[It belongs to] a series of testicular antigens that are developmental pathway proteins that [usually] aren’t expressed in normal cells, which makes them ideal targets for cancer therapies. The 2 cancers that have a high expression of MAGEA4 are synovial sarcoma and myxoid/round cell [liposarcoma]. However, between 1% and 3% of all solid tumors also express MAGEA4 on the cell surface, making it an avenue for the development of T-cell therapies and bispecific T-cell engagers.”

Solid tumors with MAGEA4 expression include non–small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, ovarian cancer, urothelial cancer, melanoma, and gastroesophageal cancers. Expression of MAGEA4 in normal tissue is limited to immune-privileged sites. The antigen is processed intracellularly, leading to peptide fragments being presented with human leukocyte antigens (HLAs) on the cell surface, which form epitopes that are weakly recognized by natural T-cell receptors (TCRs).²

Afami-Cel Sets the Precedent for Cell Therapy in Solid Tumors

Afami-cel is an autologous T-cell therapy that is designed to express a TCR targeted against a MAGEA4 peptide. Findings from a preclinical study showed that afami-cel displayed potent cytotoxic effects and effector-cytokine release against HLA-A*02/MAGEA4-expressing cancer cells.²

The FDA granted accelerated approval to afami-cel for the treatment of adult patients with unresectable or metastatic synovial sarcoma who have received prior chemotherapy; are positive for HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, or HLA-A*02:06P; and have tumors expressing MAGEA4 as determined by FDA-approved or -cleared companion diagnostic devices. The regulatory decision was supported by findings from cohort 1 of the phase 2 SPEARHEAD 1 trial (NCT04044768).³

SPEARHEAD 1 was an open-label, nonrandomized study that included 3 cohorts. Cohort 1 consisted of patients aged 16 to 75 years with HLA-A*02–positive, MAGEA4-expressing metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma who had received at least 1 prior line of chemotherapy. Patients underwent lymphodepletion and received afami-cel at a dose range of 1.0×10⁹ to 10.0×10⁹ T cells via a single intravenous infusion. The primary end point was overall response rate (ORR) in cohort 1 per RECIST 1.1, assessed by an independent review committee; secondary end points included progression-free survival (PFS), overall survival (OS), and safety.⁴

At a median follow-up of 32.6 months (IQR, 29.4-36.1), patients with synovial sarcoma (n = 44) achieved an ORR of 39% (95% CI, 24%-55%) and those with myxoid round cell liposarcoma (n = 8) experienced an ORR of 25% (95% CI, 3%-65%). Notably, the median OS among patients with synovial sarcoma was not reached (NR; 95% CI, 15.4-not estimable) and the median PFS was 3.8 months (95% CI, 2.8-6.4). The estimated 12- and 24-month OS rates in patients with synovial sarcoma and a RECIST response were 90% (95% CI, 65%-99%) and 70% (95% CI, 43%-87%), respectively.⁴

The median duration of response was 11.6 months (95% CI, 4.4-18.0) in patients with synovial sarcoma and 4.2 months (95% CI, 2.9-5.5) in patients with myxoid round cell liposarcoma. Among patients with synovial sarcoma, the overall probability of being alive and not on additional systemic treatment at 24 months was 30% (95% CI, 13%-39%).⁴

“There is a group of patients who do not respond and come off treatment rather early, but [there is another group who have] deep, durable responses on [afami-cel] for years, as long as you have a major response,” Van Tine noted. “I have patients who have been on this trial who are still on the trial from the beginning. If you can get a deep response, [it] can be incredibly durable, and this [is accompanied by a] high quality of life because there’s no more chemotherapy, no oral medications—there’s nothing other than getting surveillance scans. There’s a lot of effort to [examine] that group who don’t have a deep and durable response, understand why they don’t, and try to make it so that they can. We’re not quite sure what to add yet, but this is the work that’s ongoing.”

Safety findings from SPEARHEAD 1 showed that 100% of patients in cohort 1 who received afami-cel experienced any-grade treatment-emergent adverse effects (TEAEs). The most common any-grade TEAEs included cytokine release syndrome (CRS; 71%), decreased white blood cell count or leukopenia (27%), pyrexia (23%), and decreased neutrophil count or neutropenia (23%). Grade 3 or worse cytopenia occurred in 19% of cohort 1 and included neutropenia (10%), anemia (8%), and thrombocytopenia (6%).⁴

“With cellular therapies, we always worry about CRS,” David S. Hong, MD, deputy chair of the Department of Investigational Cancer Therapeutics in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncologyLive. “The vast majority of these patients had grade 1 or 2 [CRS], which is somewhat different than [the CRS from]chimeric antigen receptor T-cell therapies being developed in lymphoma. We’ll see what happens as more and more of these [products] get approved and enter the clinic. But overall, my experience [is that] cellular therapies in solid tumors tend to be less toxic than in lymphomas and other [hematologic malignancies].”

Notably, cohort 1 had no treatment-related deaths and no deaths within the first 30 days following afami-cel infusion. There were 28 deaths overall, all of which resulted from disease progression, according to investigators.⁴

The phase 1 study (NCT03132922) that preceded SPEARHEAD 1 examined afami-cel in patients withesophageal (n = 2), gastric (n = 1), head and neck (n = 3), ovarian (n = 9), and urothelial (n = 2) cancers as well as melanoma (n = 1), NSCLC (n = 2), synovial sarcoma (n = 16), and myxoid round cell liposarcoma (n = 2). In the modified intention-to-treat population (n = 38), the ORR was 24% (95% CI, 11.4%-40.2%), which included 7 patients with synovial sarcoma and 1 patient each with NSCLC and head and neck cancer who had a partial response. The median PFS and OS were 12.3 weeks (95% CI, 10.9-19.1) and 42.9 weeks (95% CI, 20.7-NR), respectively.²

Afami-cel is also set to be examined in the phase 1/2 pediatric basket study SPEARHEAD-3 (NCT05642455), which is enrolling patients aged 2 to 21 years with HLA-A*02–positive, MAGEA4-expressing advanced synovial sarcoma, malignant peripheral nerve sheath tumors, neuroblastoma, or osteosarcoma. Eligible patients must have received prior chemotherapy and have an ECOG performance status of 1 or less or a Lansky score of 80 or more.⁵

The primary end point is the incidence of TEAEs. Secondary end points include ORR, PFS, OS, and pharmacokinetics. The study is currently recruiting patients, and the primary completion date is estimated for October 2026.

“The hope is that we can scale [afami-cel] into more common tumor types,” Hong said. “In order for this to happen, we’ll need the vein-to-vein time of the drug to be much shorter. It currently takes approximately 6 weeks, if not longer, [to produce].”

MAGEA4-Directed Agents Beyond Afami-Cel Progress Through the Development Pipeline

MAGEA4 is being explored as a potential target for multiple novel T-cell therapies in several tumor types. IMA401 is a next-generation, half-life–extended TCR-based bispecific T-cell engager that targets both MAGEA4 and MAGEA8. The agent is being evaluated in an ongoing phase 1 study (NCT05359445) in patients with recurrent or refractory solid tumors with HLA-A*02:01–positive, MAGEA4/8-expressing disease who had received or were not eligible for all available indicated standard-of-care therapies.⁶

Initial data from this study presented during the 2024 European Society for Medical Oncology Congress showed that efficacy-evaluable patients (n = 29)—who were heavily pretreated with a median of 3 (range, 2-8) prior lines of therapy—achieved an ORR of 21%. Additionally, those with high MAGEA4/8 expression (n = 17) achieved an ORR of 29% and a disease control rate of 53%. The toxicity profile of the agent was manageable, with the most common treatment-related AEs being low-grade CRS, transient lymphopenia, and neutropenia; dose escalation in the study is ongoing.⁶

Another early-phase study, the phase 1 APOLLO trial (NCT05798897), is investigating the novel multitumor-associated antigen-specific T-cell agent MT-601 for the treatment of patients with relapsed/refractory lymphoma who did not respond to or are ineligible for anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. MT-601 uses a non–genetically modified approach to target 6 tumor antigens upregulated in lymphoma cells: survivin, PRAME, WT1, NY-ESO-1, SSX2, and MAGEA4.⁷

In April 2024, the principal investigator of the APOLLO study presented findings at the Global Summit on Hematologic Malignancies on a study participant with follicular non-Hodgkin lymphoma who had experienced 12 prior treatment failures, including with axicabtagene ciloleucel (Yescarta), after transformation to diffuse large B-cell lymphoma (DLBCL) but achieved a complete response (CR) with MT-601 and remained in CR 3 months after treatment. Another patient with DLBCL who was ineligible for CAR T-cell therapy achieved a partial response with MT-601 at 8 weeks post treatment. Updated data from a third patient with DLBCL who had experienced 4 prior failed lines of therapy, including with an anti-CD19 CAR T-cell agent, indicated that the patient remained in CR 9 months after receiving MT-601.⁷

“The most important thing to realize is that right now, we have a [MAGEA4–directed] product that is FDA approved for synovial sarcoma,” Van Tine said. “There’s going to be this new academic-private practice partnership for managing these therapies, which is new for the solid tumor doctors. There are going to be a lot of constructive conversations happening between private practices [regarding] getting access to these [therapies], testing locally, and getting treated at the center. This is going to change how oncology is practiced, but for the patients in whom it works, it’s the most transformative thing I’ve seen in my career.”

References

1. Adaptimmune receives U.S. FDA accelerated approval of Tecelra (afamitresgene autoleucel), the first approved engineered cell therapy for a solid tumor. News release. Adaptimmune Therapeutics plc. August 1, 2024. Accessed October 3, 2024. bit.ly/3BAIq1e
2. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. 2023;29(1):104–114. doi:10.1038/s41591-022-02128-z
3. FDA grants accelerated approval to afamitresgene autoleucel for unresectable or metastatic synovial sarcoma. FDA. Updated August 2, 2024. Accessed October 3, 2024. bit.ly/3Y96jFP
4. D’Angelo SP, Araujo DM, Abdul Razak AR, et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. Lancet. 2024;403(10435):1460-1471. doi:10.1016/S0140-6736(24)00319-2
5. SPEARHEAD-3 pediatric study. ClinicalTrials.gov. Updated April 24, 2024. Accessed October 3, 2024. https://clinicaltrials.gov/study/NCT05642455
6. Wermke M, Ochsenreither S, ChatterjeeM, et al. Initial safety, pharmacokinetics, and anti-tumor activity data of TCER IMA401, a MAGEA4/8-directed half-life extended TCR bispecific, in phase I dose escalation. Ann Oncol. 2024;35(suppl 2):S681-S682. doi:10.1016/j.annonc.2024.08.1060
7. Principal investigator from City of Hope National Medical Center invited to present clinical data from Marker Therapeutics APOLLO study at 11th Global Summit on Hematologic Malignancies. News release. Marker Therapeutics Inc. April 8, 2024. Accessed October 4, 2024. bit.ly/3XNlLWK