Phase I clinical trial evaluating the safety and efficacy of ADP-A2M10 SPEAR T cells in patients with MAGE-A10⁺ advanced non-small cell lung cancer

Abstract

BackgroundADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10+ tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577).MethodsEligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08–0.12×109 (dose group 1), 0.5–1.2×109 (dose group 2), and 1.2–15×109 (dose group 3/expansion) transduced cells.ResultsEleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m2 on days –5 to –2 and cyclophosphamide 1800 mg/m2 on days −5 to −4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10.ConclusionsADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing.

Structural insights into engineering a T-cell receptor targeting MAGE-A10 with higher affinity and specificity for cancer immunotherapy

“…However, counterexamples of safer engineered T-cell products are emerging from advancing clinical trials, in particular against cancer testis antigen targets such as New York esophageal squamous cell carcinoma 1 (NY-ESO-1), MAGE-A4, and MAGE-A10. [10][11][12] Increasingly, more refined preclinical safety methods are being employed to screen the cross-reactome in order to minimize the likelihood of taking to the clinic a TCR T-cell product with associated off-target reactivities. [13][14][15][16][17] This is in addition to the generic problem in target validation of avoiding on-target, off-tumor reactivity and toxicity, whereby a safe therapeutic window of target expression ensures selective targeting of tumor over normal cells.…”

“…The c796 TCR ultimately formed the basis of Adaptimmune's ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cell therapy that entered phase I/II clinical trials in a triple tumor study (melanoma, urothelial, or head and neck cancers), 18 and a non-small cell lung cancer study. 19 This TCR T-cell therapy has proven to be generally well tolerated in those clinical tests, with a manageable toxicity profile. 12 We reveal that the c796 TCR was engineered by incorporating a single conservative mutation into the parental TCR, c728, which resulted in a ~sixfold increase in binding affinity to peptide-HLA complex (pHLA) compared with the parental as measured by surface plasmon resonance.…”

“…19 This TCR T-cell therapy has proven to be generally well tolerated in those clinical tests, with a manageable toxicity profile. 12 We reveal that the c796 TCR was engineered by incorporating a single conservative mutation into the parental TCR, c728, which resulted in a ~sixfold increase in binding affinity to peptide-HLA complex (pHLA) compared with the parental as measured by surface plasmon resonance. 13 Thus, we wished to understand at the molecular level how this subtle change could affect pHLA binding.…”

“…The c796 TCR ultimately formed the basis of Adaptimmune’s ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cell therapy that entered phase I/II clinical trials in a triple tumor study (melanoma, urothelial, or head and neck cancers), 18 and a non-small cell lung cancer study. 19 This TCR T-cell therapy has proven to be generally well tolerated in those clinical tests, with a manageable toxicity profile. 12 …”

Development of an affinity-enhanced clinical candidate TCR targeting NY-ESO-1 with optimal potency and high specificity

“…As a prominent approach in immunotherapy, adoptive transfer of T cells genetically modified by T cell receptor (TCR) has demonstrated profound potential in clinical trials for both hematological malignancies and solid tumors. 1–4 Nevertheless, the successful development of TCR-engineered T (TCR-T) cell therapy remains challenging owing to its efficacy and safety issues.…”