Commentary

Article

Afami-Cel Shows Durable Persistence and Tumor-Killing Abilities in Synovial Sarcoma

Author(s):

Fact checked by:

Treatment with afami-cel was associated with long-term persistence in the periphery that led to clinical benefit in patients with synovial sarcoma.

lertsakwiman– stock.adobe.com

lertsakwiman– stock.adobe.com

Treatment with afamitresgene autoleucel (afami-cel; Tecelra) was associated with long-term persistence in the periphery that led to clinical benefit in patients with synovial sarcoma, according to findings from translational analyses of the phase 2 SPEARHEAD-1 trial (NCT04044768) presented at the 2024 CTOS Annual Meeting.1

SPEARHEAD-1 investigators found that afami-cel accumulated after infusion and reached peak concentration at a median of 7 days post-infusion. Furthermore, afami-cel was detected in patients at over 3 years post-infusion. The median terminal half-life of the product was 152 days; this value was 263 days in responders and 84 days in non-responders. Investigators noted that afami-cel persistence tended to plateau over time in several patients, which was consistent with the durable persistence findings. Notably, 1 patient had an afami-cel level below quantification limits at any time point.

Afami-Cel’s Mechanism of Action and FDA Approval

Afami-cel is an engineered high-affinity TCR T-cell product that expresses an exogenous T-cell receptor and targets a peptide from HLA-presented MAGE-A4—a cancer antigen that is upregulated in certain tumors. Patient eligibility for afami-cel is restricted to patients with tumors that express MAGE-A4 and have HLA molecules that will react with the afami-cel T-cell receptor.

Cohort 1 of the open-label, international SPEARHEAD-1 trial evaluated the efficacy and safety of afami-cel in 44 patients with HLA-A*02–positive, MAGE-A4–expressing, advanced or metastatic synovial sarcoma.1,2 Patients received 1 infusion of afami-cel following lymphodepleting chemotherapy.

In this trial, afami-cel elicited an overall response rate of 39% (95% CI, 24%-55%).2 The median duration of response was 11.6 months (95% CI, 4.4-18.0).1

Regarding safety, cytopenias were the most common grade 3 or higher adverse effect.2 Additionally, most patients developed cytokine release syndrome (CRS), 1 of whom had grade 3 CRS.

On August 2, 2024, the FDA granted accelerated approval to afami-celfor the treatment of adult patients with unresectable or metastatic synovial sarcoma who have received prior chemotherapy; have HLA-A*02:01P–, HLA-A*02:02P–, HLA-A*02:03P–, or HLA-A*02:026P–positive disease; and whose tumors express MAGE-A4 as determined by FDA-approved diagnostics or cleared companion diagnostic devices.3 The decision was supported by data from SPEARHEAD-1, and afami-cel is the first engineered cell therapy to be approved by the FDA for the treatment of patients with solid tumors.

Translational Research Goals

Investigators conducted translational analyses to determine how the mechanism of action of afami-cel induced the clinical responses seen in SPEARHEAD-1.1 Blood samples from the periphery of afami-cel–treated patients were assessed, along with tumor biopsies taken before and after treatment.

The objectives of these analyses were to identify how afami-cel induces long-term responses and to collect other findings to support the product’s intended mechanism of action.

Additional Persistence Findings

At a data cutoff of March 29, 2023, additional data from the translational research showed that patients who achieved an objective response experienced greater long-term pharmacokinetic exposure to afami-cel at an area under the curve (AUC) of 0 to 12 months vs non-responders (P < .001). Greater long-term pharmacokinetic exposure also correlated with significantly longer progression-free survival (PFS). Patients with an AUC of 0 to 12 months at or above the median (n = 17) were associated with longer PFS compared with patients with an AUC of 0 to 12 months below the median (n = 16; P < .05).

After infusion, both CD4- and CD8-positive afami-cel T cells developed phenotypes of memory T cells, defined as T cells that can persist long term, which express unique phenotypic markers. Flow cytometry showed that expression of memory markers increased on afami-cel after infusion, indicating that conversion to memory phenotypes was consistent with long-term afami-cel persistence. Flow cytometry also found that afami-cel demonstrated consistently low expression of T-cell exhaustion phenotypic markers beyond 2 years post-infusion; this finding was consistent with the product’s cytolytic functionality retention and long-term persistence.

Case Study Findings

A case study showed that 1 patient who received afami-cel achieved a sustained response, including tumor cell killing, lasting longer than 3.7 years post-infusion. Two of this patient’s 3 target lesions completely resolved, and 1 lesion had a partial response (PR). Lesion 2 shrank more than 3 years post-infusion. Investigators noted that this delayed tumor shrinkage indicates that afami-cel retains a long-term ability to kill tumor cells.

Through flow-based sorting, investigators detected and isolated afami-cel from this patient and used an ex vivo killing assay, which showed that the isolated afami-cel retained its killing ability 3.3 years post-infusion.

Investigators noted that similar long-term afami-cel potency was also seen in other patients.

Afami-Cel’s Activity in the Tumor Microenvironment

Using RNA in situ hybridization, investigators detected afami-cel’s infiltration of tumoral and stromal regions in 30 out of 32 tested post-infusion biopsies. This analysis demonstrated that afami-cel can infiltrate solid tumors, which is consistent with its intended mechanism of action.

Afami-cel was also shown to activate endogenous immune responses through T-cell infiltration in 23 synovial sarcoma tumors, including 4 that had a PR, 15 that had stable disease, and 4 that had progressive disease. Investigators saw a significant increase in the densities of all CD3-positive T cells in the tumor beyond afami-cel cells (P < .001) that was attributed to an influx of afami-cel transgene­–negative endogenous T cells in the tumors after treatment. Levels of Ki67-positive CD8-positive T-cells (which are indicative of proliferation) and Grb-positive CD8-positive T cells (which are indicative of killing ability) also increased following afami-cel infusion.

Investigators explained that these findings show that beyond directly killing tumor cells, afami-cel activates a patient-driven antitumor response by inflaming the tumor microenvironment and recruiting endogenous T cells that can proliferate and kill tumor cells.

Disclosures: Dr Druta reported receiving consultancy fees and advisory board fees from Aadi Bioscience, Adaptimmune, Daiichi Sankyo, and Deciphera Pharmaceuticals. All other study authors are employees of, and may hold stock/options in, Adaptimmune. The study was sponsored by Adaptimmune.

References

  1. Druta M, Dupont CD, Bath N, et al. Translational analyses reveal mechanisms of afami-cel’s anti-tumor activity in synovial sarcoma. Presented at: 2024 CTOS Annual Meeting. November 13-16, 2024; San Diego, California.
  2. 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
  3. 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. August 1, 2024. Accessed November 20, 2024. https://www.adaptimmune.com/investors-and-media/news-center/press-releases/detail/271/adaptimmune-receives-u-s-fda-accelerated-approval-of
Related Videos
David Schiff, MD
Timothy Gershon, MD, PhD
Jordan Hansford, MD
James J. Harding, MD, associate attending physician, Memorial Sloan Kettering Cancer Center
J. Bradley Elder, MD
Rimas V. Lukas, MD
Adam E. Singer, MD, PhD, Health Sciences Clinical Instructor, medicine, division lead, kidney cancer, Division of Hematology/Oncology, UCLA Health
Diane Reidy-Lagunes, MD, vice chair, Oncology Operations, Regional Care Network, Memorial Sloan Kettering Cancer Center
Shubham Pant, MD, MBBS
Kevin Kalinsky, MD, MS, professor, Department of Hematology and Medical Oncology, director, Division of Medical Oncology, Department of Hematology and Medical Oncology, Emory University School of Medicine; Louisa and Rand Glenn Family Chair in Breast Cancer Research, director, Glenn Family Breast Center, director, Breast Medical Oncology, Winship Cancer Institute of Emory University