Tecelra (afamitresgene autoleucel)

In August 2024, afamitresgene autoleucel was approved in the USA under accelerated approval for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P or -A*02:06P positive and whose tumour expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This article summarizes the milestones in the development of afamitresgene autoleucel leading to this first approval for the treatment of advanced synovial sarcoma.

P=N/A, N=0, Available, Adaptimmune

"Thermo Fisher Scientific Inc...announced that its SeCore CDx HLA A Sequencing System has been granted 510(k) clearance by the United States Food and Drug Administration (FDA) for use as a companion diagnostic with TECELRA (afamitresgene autoleucel), Adaptimmune’s newly approved T-cell receptor (TCR) therapy for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. Synovial sarcoma is a rare, soft tissue cancer that most commonly impacts young adults."

"Agilent Technologies Inc...announced that it has received FDA approval for the use of MAGE-A4 IHC 1F9 pharmDx (SK032) as a diagnostic tool to aid in identifying patients with synovial sarcoma who may be eligible for treatment with TECELRA (afamitresgene autoleucel, also known as afami-cel or ADP-A2M4), a MAGE-A4-directed engineered TCR T-Cell therapy."

Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies.

P1/2, N=20, Recruiting, Adaptimmune | Not yet recruiting --> Recruiting

P1, N=71, Active, not recruiting, Adaptimmune | N=52 --> 71 | Trial completion date: Sep 2035 --> Sep 2032

Conclusions The CLB MAGE-A4 immunostaining conditions were successfully adjusted and bridged to reach concordance with the clinical trial assay. This allowed the accurate assessment of the prognostic value of MAGE-A4 in SyS.

Lymphodepleting chemotherapy consisting of fludarabine (30 mg/m^2/day for 4 days) and cyclophosphamide (600 mg/m^2/day for 3 days) will be administered beginning one week prior to afami-cel infusion... N/A. Submitting under Trials in Progress.

P2, N=120, Recruiting, Adaptimmune | N=90 --> 120 | Trial completion date: Nov 2034 --> Apr 2038

This report suggests that afami-cel in combination with LDRT safely enhanced clinical benefit. This provides evidence for further exploring the benefit of LDRT in TCR-T cell therapy.

Van Tine, et al. Paper 61: CTOS 2022; Vancouver, Canada

Introduction: Affinity-enhanced T-cell receptor (TCR) T-cell therapies targeting the intracellular cancer testis antigen MAGE-A4 have shown encouraging results in adults with advanced solid cancers.1,2 Here we explore how TCR T-cell therapy manufacturing process evolution may modulate the function of ADP-A2M4CD8, the next generation counterpart of afamitresgene autoleucel (afami-cel; formerly ADP-A2M4), using single-cell RNA sequencing (scRNA-seq) and in vitro functional assessment. Whole-transcriptome, single-cell investigation of the cellular subsets produced during manufacturing of afami-cel and ADP-A2M4CD8 indicate that infusion of cells with a less cytotoxic GEP does not prevent broad anti-tumor efficacy and may correspond with beneficial characteristics. 1. Van Tine BA, et al.

P1/2, N=20, Not yet recruiting, Adaptimmune | Trial completion date: Apr 2038 --> Jun 2038

Van Tine, BA et al. Paper 61 presented at: CTOS 2022; Vancouver, BC, Canada.

Purpose: This abstract presents data on two cell therapies being tested in clinical trials, afamitresgene autoleucel (afami-cel; formerly ADP-A2M4) and its next-generation counterpart ADP-A2M4CD8, to inform nurses on new promising therapies...SURPASS (NCT04044859) is a Phase 1, first-in-human trial evaluating ADP-A2M4CD8 as monotherapy or in combination with nivolumab in multiple tumor types... Nurses play key roles at every stage in the administration of T-cell therapy. Understanding advances in cancer treatment and associated clinical data will better prepare nurses to effectively manage patients that may benefit from these novel therapies.

In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

P1/2, N=20, Not yet recruiting, Adaptimmune

P2, N=90, Recruiting, Adaptimmune | Trial completion date: Apr 2038 --> Nov 2034 | Trial primary completion date: Jan 2023 --> Oct 2021

P2, N=90, Recruiting, Adaptimmune | Trial completion date: Nov 2034 --> Apr 2038

P2, N=90, Recruiting, Adaptimmune | Trial primary completion date: May 2022 --> Jan 2023

Preliminary translational findings appear to demonstrate a potent and functionally active afami-cel MP which aligns with the promising clinical activity of afami-cel in the SPEARHEAD-1 trial to be presented at this congress. Ongoing detailed evaluation of translational datasets, including potential relationships between cell kinetics and pharmacodynamic effects (IFN signaling), and sarcoma TME profiling, aim to provide a deeper translational understanding of the mechanisms of afami-cel response. An update will be available at the time of the congress.[1] D Angelo et al.

These preliminary data demonstrate afami-cel is efficacious in heavily pre-treated patients with synovial sarcoma. Objective responses are reported across a wide range of MAGE-A4 antigen levels, and deep and durable responses have been observed. To date, the safety profile of afami-cel has been favorable, with mainly low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities.

P2, N=90, Recruiting, Adaptimmune | Trial primary completion date: Oct 2021 --> May 2022

P2, N=0, Withdrawn, Adaptimmune | N=10 --> 0 | Trial completion date: Oct 2036 --> Dec 2021 | Recruiting --> Withdrawn | Trial primary completion date: Apr 2022 --> Dec 2021

P1, N=52, Active, not recruiting, Adaptimmune | Recruiting --> Active, not recruiting

scRNASeq gene expression profiles of first-gen ADP-A2M4 product manufactured with AKTi revealed the AKTi-expanded T-cells had a greater proliferation or an enhanced memory phenotype; scRNASeq analyses are ongoing for the ADP-A2M4CD8 product.An increase in IL-12 levels (MSD) in serum post-infusion suggests that endogenous immune cells are being activated, further resulting in increased levels of IFN gamma (MSD) secretion relative to patients who received first-gen product. These enhanced products improve CD4+ T-cell killing, release more inflammatory cytokines, proliferate more robustly with an early memory phenotype, and better engage the patient‘s endogenous immune system when compared to first-gen products or next-gen manufactured without AKTi. Trial Registration NCT04044859

ADP-A2M4, a specific peptide enhanced affinity receptor (SPEAR) T-cell therapy directed towards HLA-A*02-restricted peptides, is being tested in Adaptimmune clinical trials to evaluate safety and antitumor activity in patients with synovial sarcoma...Prior to infusion, patients received lymphodepletion with cyclophosphamide and fludarabine...An understanding of clinical trial data will prepare nurses to provide evidence-based education on associated risks/benefits. In addition, clinical practice with the synovial sarcoma population can be enhanced when nurses are equipped with information associated with the administration of this novel therapy.

P2, N=90, Recruiting, Adaptimmune | N=45 --> 90 | Trial primary completion date: Jan 2022 --> Sep 2021

P1, N=52, Recruiting, Adaptimmune | Trial primary completion date: Sep 2020 --> Sep 2032

No abstract available

Prior to infusion, pts receive lymphodepletion with fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 3 days. Results As of 16 July 2020, 5 pts (1 with MRCLS, 2 with esophagogastric junction [EGJ] cancers, 1 with ovarian cancer, and 1 with head and neck cancer) were treated with ADP-A2M4 CD8 (range ~1 to 5.7 billion transduced cells)...Translational data and early clinical results indicate that co-expression of the CD8α co-receptor on CD4+ SPEAR T-cells may increase the potency of the product by conferring additional killing activity to the helper T-cell subset. This dose escalation trial is ongoing and updated clinical and translational data will be presented.

Prior to infusion, pts receive lymphodepletion with fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 600 mg/m2/day for 3 days. Results As of 16 July 2020, 5 pts (1 with MRCLS, 2 with esophagogastric junction [EGJ] cancers, 1 with ovarian cancer, and 1 with head and neck cancer) were treated with ADP-A2M4 CD8 (range ~1 to 5.7 billion transduced cells)...Translational data and early clinical results indicate that co-expression of the CD8α co-receptor on CD4+ SPEAR T-cells may increase the potency of the product by conferring additional killing activity to the helper T-cell subset. This dose escalation trial is ongoing and updated clinical and translational data will be presented.

Pts without a response by Wk 7 will proceed to Part B. Pts who respond to pembro after 3 cycles will continue treatment in Part A until PD when they will become eligible for ADP-A2M4 treatment in Part B. Part B: Pts will undergo lymphodepleting chemotherapy w/ fludarabine and cyclophosphamide prior to receiving ADP-A2M4 at a dose range of 1x109 to 10x109 transduced T-cells...Funding: Adaptimmune. Clinical trial identification: NCT03132922.

P2, N=10, Recruiting, Adaptimmune | Not yet recruiting --> Recruiting

P2, N=10, Not yet recruiting, Adaptimmune

Overall, this work represents the development of an allogeneic hiPSC derived platform, with limited genome editing, that permits the production of SPEAR iT-cells with potential therapeutic value. The identification of a suitable locus for targeted integration of a defined TCR/SPEAR enables the future production of multiple iT-cell banks directed against specific tumor associated antigens in a defined and reproducible manner.