639 BASECAMP-1: Leveraging HLA loss of heterozygosity in solid tumors by NGS to identify patients with relapsed solid tumors for future CEA and MSLN logic-gated Tmod™ CAR T-cell therapy

Abstract

<h3>Background</h3> Solid tumors comprise &gt;90% of cancers. Non-small cell lung cancer (NSCLC), metastatic colorectal cancer (CRC), and pancreatic cancer are the leading causes of cancer-related mortality (5-year overall survival: 26%, 15%, and 11%, respectively).¹ Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies.^2,3 However, translating engineered T-cell therapies to solid tumors has proven to be challenging due to a lack of tumor-specific targets that can discriminate cancer cells from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and mesothelin (MSLN) CARs resulted in dose-limiting on-target, off-tumor toxicities.^4,5 To create a therapeutic safety window, Tmod CAR T-cell therapy utilizes dual-signaling receptors to create a robust logic gate capable of killing tumor cells, while leaving healthy cells intact.^6,7 The 2 receptors in Tmod CAR T-cell therapy comprise an activator that recognizes an antigen on the surface of tumor cells that may also be present on normal cells, such as CEA and MSLN, and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells (figure 1).^8,9 Human leukocyte antigen (HLA) loss of heterozygosity (LOH) offers a definitive tumor versus normal discriminator target for CAR T-cell therapy.¹⁰ The frequency of HLA LOH among advanced NSCLC, CRC, and pancreatic cancers in the Tempus real-world dataset is 16.3% with a range of 15.6%-23.1%.¹¹ LOH can be reliably detected using the Tempus xT-Onco next-generation sequencing (NGS) assay.^12,13 Different activator/blocker combinations can be engineered with the Tmod platform technology and may be applied to T cells and natural killer cells in autologous and allogeneic settings. BASECAMP-1 is a currently enrolling observational study with key objectives: 1) To identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) Subsequent apheresis and manufacturing feasibility for the future EVEREST CEA or MSLN Tmod CAR T-cell studies. <h3>Methods</h3> BASECAMP-1 (NCT04981119) patient eligibility has 2 parts (figure 2): 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central NGS. If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed for somatic mutations by xT-Onco NGS testing; 2) If the tumor demonstrates HLA-A*02:01 LOH and the patient is eligible after screening, the patient will undergo apheresis. Banked T cells will be available for the autologous EVEREST Tmod CAR T-cell therapy interventional study to reduce waiting time at relapse. <h3>Trial Registration</h3> ClinicalTrials. gov, NCT04981119 <h3>References</h3> American Cancer Society. <i>Cancer Facts &amp; Figures 2022</i>. Atlanta: American Cancer Society; 2022. Locke F, Miklos D, Jacobson C, <i>et al</i>. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. <i>N Engl J Med</i>. 2022;<b>386</b>(7):640-654. Maude S, Laetsch T, Buechner J, <i>et al</i>. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. <i>N Engl J Med</i>. 2018;<b>378</b>(5):439-448. Parkhurst M, Yang J, Langan R, <i>et al</i>. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;<b>19</b>(3):620-626. Haas AR, Tanyi JL, O’Hara MH, <i>et al</i>. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers.<i> Mol Ther</i>. 2019;<b>27</b>(11):1919-1929. Hamburger A, DiAndreth B, Cui J, <i>et al</i>. Engineered T cells directed at tumors with defined allelic loss. <i>Mol Immunol</i>. 2020;<b>128</b>:298-310. DiAndreth B, Hamburger AE, Xu H, Kamb A. The Tmod cellular logic gate as a solution for tumor-selective immunotherapy. <i>Clin Immunol</i>. 2022;<b>241</b>:109030. Sandberg ML, Wang X, Martin AD, <i>et al</i>. A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo. <i>Sci Transl Med</i>. 2022;<b>14</b>(634):eabm0306. Tokatlian T, Asuelime GE, Mock JY, <i>et al</i>. Mesothelin-specific CAR-T cell therapy that incorporates an HLA-gated safety mechanism selectively kills tumor cells. <i>J Immunother Cancer</i>. 2022;<b>10</b>(1):e003826. Hwang MS, Mog BJ, Douglass J, <i>et al</i>. Targeting loss of heterozygosity for cancer-specific immunotherapy. <i>Proc Natl Acad Sci U S A</i>. 2021;<b>118</b>(12):e2022410118. Simeone DM, Hecht JR, Patel SP, <i>et al</i>. BASECAMP-1: Leveraging human leukocyte antigen (HLA) loss of heterozygosity (LOH) in solid tumors by next-generation sequencing (NGS) to identify patients with relapsed solid tumor for future logic-gated Tmod CAR T-cell therapy. Poster presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago, IL. Abstract #TPS2676. Perera J, Mapes B, Lau D, <i>et al</i>. Detection of human leukocyte antigen class I loss of heterozygosity in solid tumor types by next-generation DNA sequencing. <i>J Immunother Cancer</i>. 2019, <b>7</b>(suppl 1):P103. Hecht JR, Kopetz S, Patel SP, <i>et al</i>. Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity. <i>J Clin Oncol</i>. 2022;<b>40</b>(4_suppl):190-190. <h3>Ethics Approval</h3> The study was approved by site IRBs