Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors

Abstract

Background: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://ichgcp.net/clinical-trials-registry/NCT02989064" title="See in ClinicalTrials.gov">NCT02989064).

Methods: Eligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1×109 and >1.2 to 6×109 transduced cells, respectively, and an expansion group receiving 1.2 to 15×109 transduced cells.

Results: Ten patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade ≥3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group.

Conclusions: ADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing.

Keywords: ADP-A2M10; HNSCC; MAGE-A10; TCR; adoptive cellular therapy; melanoma; urothelial carcinoma.

Conflict of interest statement

ABG: holds stock options in Adaptimmune. AS, DB, DM, EN, FB, JB, J-MN, JS, RB, RW, SF, and ZW: employees of Adaptimmune. DH: research/ grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Deciphera, Eisai, Erasca, Fate Therapeutics, Genentech, Genmab, Infinity, Kite, Kyowa, Lilly, LOXO, MedImmune, Merck, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, Turning Point Therapeutics, Verastem, and VM Oncology; compensation for travel, accommodations, and expenses from AACR, ASCO, Bayer, Genmab, SITC, and Telperian; consulting, speaker, or advisory roles for Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Atheneum, AUM Biosciences, Axiom, Barclays, Baxter, Bayer, Boxer Capital, BridgeBio, CDR-life AG, COG, COR2ed, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, and Ziopharm; other ownership interests in OncoResponse (Founder) and Telperian Inc (Advisor). ED: grant/research support from Aileron Therapeutics, Amgen, Aprea Therapeutics, Astex Pharmaceuticals, Bayer HealthCare Pharmaceuticals Inc., Bellicum Pharmaceuticals, BOLT Therapeutics, Compugen Ltd, Immunocore LTD, Immunomedics, Mereo BioPharma 5 Inc, NCI, PMV Pharma, Sanofi, SeaGen, TRACON Pharmaceuticals Inc., Triumvira, and Unum Therapeutics; advisory board for BOLT Therapeutics. MB: grant/contract funding for investigator-initiated clinical trials from Merck and Takara Bio; advisory boards for Adaptimmune, BMS, EMD Serono, GlaxoSmithKline, Immunocore, Instil Bio, Iovance, Merck, Novartis, Pfizer, and Sanofi; has attended speaking engagements for BMS, Merck, Novartis, and Pfizer; Safety Review Committees for Adaptimmune and GlaxoSmithKline. MF: consultant for Arcellx, BMS, Iovance, Kite, and Novartis. PF: employee of Adaptimmune; holds stock in Adaptimmune and Bristol-Myers Squibb; has received compensation for travel and congress meetings. RS: research support from Amgen and Merck; has received fees as a consultant or SAB member from Array Biopharma, Asana Biosciences, AstraZeneca, BMS, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, and Replimune. RP: grant funding from Janssen; personal fees from AstraZeneca, Bayer, BMS, Dendreon, EMD, Genentech/ Roche, Genomic Health, Jounce Therapeutics, Merck, Sanofi, and Serono/Pfizer; nonfinancial support from BMS and Genentech/Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Adaptimmune Ltd. The funder had the following involvement with the study: study design and analysis and interpretation of the data.

Copyright © 2022 Hong, Butler, Pachynski, Sullivan, Kebriaei, Boross-Harmer, Ghobadi, Frigault, Dumbrava, Sauer, Brophy, Navenot, Fayngerts, Wolchinsky, Broad, Batrakou, Wang, Solis, Duose, Sanderson, Gerry, Marks, Bai, Norry and Fracasso.

Figures

Figure 1

Study design. HLA, human leukocyte antigen; IHC, immunohistochemical; MAGE, melanoma-associated antigen; PD, progressive disease; SPEAR, specific peptide enhanced affinity receptor.

Figure 2

ADP-A2M10 were detected in peripheral blood and tumor tissue after infusion. (A) Persistence of ADP-A2M10 was measured by quantitative PCR of the Psi element sequence in genomic DNA extracted from peripheral blood mononuclear cells. Data points are colored by response. (B) Representative fields for detection of CD3+ and/or ADP-A2M10 TCR+ cells by CD3 immunohistochemical/RNA in situ hybridization assay in tumor tissue of patient 9 collected within 12 weeks after infusion. In the right image, CD3+ cells are shown in teal, ADP-A2M10 TCR+ cells are shown in purple, and nuclei are shown in light blue (hematoxylin stain). (C) Result table for CD3 immunohistochemical/RNA in situ hybridization duplex assays reporting the detection of ADP-A2M10 in two of four post-infusion tumor samples collected from the study patients. H&E, hematoxylin and eosin stain; HNSCC, head and neck squamous cell carcinoma; Mel, melanoma; NE, not evaluable; PD, progressive disease; SD, stable disease; TCR, T-cell receptor; UC, urothelial carcinoma.

Figure 3

Variability of MAGE-A10 and PD-L1 expression in tumor tissue across the study patients. Pre-infusion (screening and baseline) and post-infusion biopsies collected within 12 weeks after infusion were used for (A) MAGE-A10 expression and (B) PD-L1 expression evaluation. (A) MAGE-A10 expression was assessed by MAGE-A10 immunohistochemical staining and plotted as percentage of tumor cells with 1+, 2+ and 3+ intensities. Horizontal lines designate the cut-off of 10% of tumor with ≥1+ intensity of staining. (B) PD-L1 expression was assessed using PD-L1 IHC 22C3 pharmDx assay and plotted in terms of CPS. (A, B) Data points are colored by response. Patient IDs are indicated by shape. CPS, Combined Positive Score; MAGE, melanoma-associated antigen; NE, not evaluable; PD, progressive disease; PD-L1, programmed death ligand 1; Pre, pre-infusion; SD, stable disease.