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Prospective BASECAMP-1 experience in patients with gastrointestinal (GI) cancer: Identifying patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for a future therapeutic trial exploiting LOH as a tumor vulnerability

Prospective BASECAMP-1 experience in patients with gastrointestinal (GI) cancer: Identifying patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for a future therapeutic trial exploiting LOH as a tumor vulnerability

Authors :
J. Randolph Hecht
Scott Kopetz
Theodore Welling
Maria Pia Morelli
Julian R. Molina
Kedar Kirtane
Paul Eliezer Oberstein
Daniel R. Greenwald
Yi Lin
Armen Mardiros
Karl Beutner
Ariane Lozac'hmeur
Ameen Salahudeen
Kirstin B. Liechty
Judy Vong
Eric Wai-Choi Ng
David G. Maloney
William Y. Go
John Sutton Welch
Diane M. Simeone
Source :
Journal of Clinical Oncology. 41:209-209
Publication Year :
2023
Publisher :
American Society of Clinical Oncology (ASCO), 2023.

Abstract

209 Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal cancers are the leading causes of GI cancer–related mortality (5-y survival: 15%, 3%, and 5%-6%, respectively) (ACS 2022). HLA LOH is a recurrent mechanism of immune escape observed in 15%-20% of GI cancers (Hecht R., ASCO GI 2022). The Tmod platform is a logic-gated chimeric antigen receptor (CAR) T-cell modular system, comprising a carcinoembryonic antigen (CEA)- or mesothelin (MSLN)-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor. Both in vitro/in vivo, Tmod CAR T therapy kills cells with HLA-A*02 LOH (tumor) without harming cells with retained HLA-A*02 expression (normal). However, HLA-A*02 LOH can only be therapeutically exploited if patients are identifiable through a feasible and timely clinical workflow. Methods: We established a biobanking protocol (BASECAMP-1, NCT04981119) to determine whether HLA-A*02 LOH patients can be prospectively identified. Patients with CRC, PANC, or non-small cell lung cancer (NSCLC), and a high risk for incurable relapse, were screened first using a standard HLA assay. Heterozygous HLA-A*02 positive tumor samples were then assessed for LOH using a bioinformatic algorithm applied via the Tempus xT platform. Results: As of Sep 1, 2022, 83 patients were consented at 4 institutions. HLA status was obtained from 70 patients and 28 were identified as HLA-A*02:01 heterozygous (40%; expected frequency based on USA NMDP data, 27.6%). LOH results were available for 16 patients; 4 LOH-positive patients were identified (25%, 2 PANC, 2 NSCLC). The LOH assay sensitivity declines below a tumor purity of 40% (Hecht R., ASCO GI 2022). Six patients had a tumor purity of 20% (all with PANC, a tumor known for high stromal content), limiting possible LOH detection. The impact of tumor purity on LOH sensitivity was highlighted in a patient with a low initial sample tumor purity (30%) that resulted in a 41% probability of HLA-A*02:01 LOH (below positive threshold). A second sample with a higher tumor purity (70%), obtained from formalin-fixed, paraffin-embedded sections, resulted in a 92% probability of HLA-A*02:01 LOH (positive). Conclusions: BASECAMP-1 prospective identification of HLA-A*02 LOH is feasible in the real-world setting. The frequencies of the HLA-A*02 allele and of HLA-A*02 LOH in this cohort mirrored expected population frequencies. LOH results can be obtained within a clinically feasible workflow and timeframe, although samples with a < 40% tumor purity have a reduced sensitivity for LOH detection, an issue recurrently observed in patients with PANC. The BASECAMP-1 strategy enables prospective identification of appropriate patients for future therapeutic clinical trials using Tmod CEA and MSLN logic-gated CAR T cells. Clinical trial information: NCT04981119 .

Subjects

Subjects :
Cancer Research
Oncology

Details

ISSN :
15277755 and 0732183X
Volume :
41
Database :
OpenAIRE
Journal :
Journal of Clinical Oncology
Accession number :
edsair.doi...........bd8c853127ee8e5bd6088306a421171f
Full Text :
https://doi.org/10.1200/jco.2023.41.4_suppl.209