Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors.

Abstract

102 Background: MAGE-A4 is a cancer/testis antigen with expression in many solid tumors promoting cell growth by preventing cell cycle arrest and apoptosis. This study (NCT03132922) evaluated safety and efficacy of SPEAR T-cells directed against the MAGE-A4 peptide expressed in 9 tumor types. Methods: This Phase I dose-escalation, expansion trial evaluated patients (pt) who were HLA-A*02 positive with advanced cancers that expressed the MAGE-A4 protein. Autologous T-cells from eligible patients were isolated, transduced with a lentiviral vector containing the MAGE-A4c1032 TCR, and expanded. Prior to ADP-A2M4 infusion, pts received a lymphodepletion regimen of cyclophosphamide and fludarabine. Cohorts 1, 2, 3, and expansion were to receive transduced cell doses of up to: 0.12 × 109, 1.2 × 109, 6 × 109, and 10 x 109, respectively. Results: As of 23 October 2019, 9 pts were treated in dose escalation with no DLTs; 25 pts were treated in expansion. Median age was 56.5 yr (range: 31-78). All pts received prior chemotherapy. Most common ( > 30%) AEs ≥Grade 3 were lymphopenia, leukopenia, neutropenia, anemia, thrombocytopenia, and febrile neutropenia. Two pts had trial-related deaths (aplastic anemia and CVA) leading to modification of the lymphodepletion regimen and eligibility criteria. In Cohort 3/expansion (28 pts), Best Overall Response was PR (7), SD (11), PD (5), non-evaluable (5). All PRs, at the time of data cut-off, were in patients with synovial sarcoma. Transduced T-cells were detectable in all patients. Tumor infiltration of SPEAR T-cells was detectable in several cohort 3/expansion pts. Conclusions: The Phase I single agent ADP-A2M4 trial will complete enrollment shortly and updated data will be presented. ADP-A2M4 shows promising efficacy and a manageable safety profile at a dose range of 1.2 – 10 × 109. Clinical activity in various tumors has led to a separate on-going low dose radiation sub-study of this trial, a Phase II trial in sarcoma (SPEARHEAD-1, NCT04044768), and a Phase I trial (SURPASS, NCT04044859) with ADP-A2M4CD8, a next-generation SPEAR T-cell targeting MAGE-A4. Clinical trial information: NCT03132922.

Targeting cancer testis antigens in synovial sarcoma

“…All seven of the patients who had a response had SS. 74 Longer-term follow-up of patients with SS specifically demonstrated a response rate of 44%, with durable responses lasting at least 6 months. 75 Preliminary translational analysis showed that MAGE-A4 expression levels and the total cell infusion dose correlated with response.…”

“…Older patients or those who have received multiple highly myelosuppressive regimens may have less bone marrow reserve and be less likely to tolerate the more effective higher intensity regimens, with fatal aplastic anemia reported in early studies. 74 75 …”

Addressing Resistance to Immune Checkpoint Inhibitor Therapy: An Urgent Unmet Need

“…Other novel approaches to treating cancer include the combination of ICIs with immunostimulatory agents [380,381], probiotics [382,383], adoptive T-cell therapy [106,[384][385][386], cancer vaccines [106,387], nanoparticlemediated thermolysis [388][389][390] and electrochemotherapy [391,392]. Further investigation of these combination strategies in the clinic and in larger patient populations is warranted.…”

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

“…A recent update on this trial was presented at the 2020 ASCO annual meeting. Hong et al reported that 7 of 28 patients in the expansion cohort had partial responses, all patients with synovial sarcoma [ 69 ]. Data from this study led to the activation of a phase II trial of ADP-A2M4 SPEAR T cells in advanced synovial sarcoma or myxoid/ round cell liposarcoma (NCT04044768).…”