TAP deficiency leads to poor cell surface expression of peptide–MHC-I complexes, but often reveals novel T cell epitopes associated with impaired peptide processing (TEIPP). Emmers, Welters and Dietz et al. developed a synthetic long-peptide vaccine from LRPAP1, and carried out a first-in-human dose escalation study in 26 HLA-A*02:01+ checkpoint-resistant patients with stage IV NSCLC. One cohort received the highest dose of TEIPP vaccine plus pembrolizumab. LRPAP1-specific CD8+ and CD4+ T cells were detected in 83% and 62% patients, respectively. The vaccine was well tolerated, and 1 PR, 8 SD, and 2 MR were observed in 24 vaccinated patients.
Contributed by Katherine Turner
ABSTRACT: Functional loss of the intracellular peptide Transporter associated with Antigen Processing (TAP) fosters resistance to T-cell based immunotherapy. We discovered the presentation of an alternative set of shared tumor antigens on such escaped cancers and developed a LRPAP1 synthetic long peptide vaccine (TEIPP24) to stimulate T-cell immunity. In this first-in-human multicenter dose-escalation study with extension cohort, HLA-A*0201-positive patients with non-small cell lung cancer progressive after checkpoint blockade were treated with TEIPP24 (NCT05898763). Dose escalation followed an adapted 3 + 3 scheme where in each cohort six patients received the TEIPP24 peptide emulsified in Montanide ISA-51 at either 20, 40, 100 µg of peptide, subcutaneously injected three times every three weeks in alternating limbs. The extension cohort of six patients received the highest safe dose of TEIPP24 combined with the PD-1 checkpoint blocker pembrolizumab. The primary objectives of the study were safety, tolerability and immunogenicity of the TEIPP24 vaccine. Secondary objectives included the evaluation of specificity and immune modulatory effects of the vaccine, antigen and immune status of the patients, progression free (PFS) and overall survival (OS) and radiological tumor response rate and duration. A total of 26 patients were enrolled across 2 institutions. Treatment was well tolerated, and vaccine-induced LRPAP1-specific CD8+ T cells were detected in 20 of 24 evaluable patients (83%). In 13 of 21 tested cases (62%) vaccine-specific CD4+ T cells were also detected. The increase in activated polyfunctional CD8+ effector T cells was influenced by vaccine dose, number of vaccines administered, induction of a CD4+ T-cell response, and the pre-existing frequency of monocytic cells. Co-administration of pembrolizumab resulted in the ex-vivo detection of activated (HLA-DR+ , PD-1+ , ICOS+ ) LRPAP1-specific CD8+ T cells. The observation of one PR, 8 stable diseases and 2 mixed responses in 24 evaluable patients after vaccination, correlated with a stronger vaccine-induced CD8+ T-cell response to this single epitope from this new class of cancer antigens.
Author Info: (1) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden University Medical
Author Info: (1) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (2) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (3) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (4) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (5) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (6) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (7) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (8) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (9) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (10) Department of Pulmonary Disease, Leiden University Medical Center, Leiden, The Netherlands. (11) Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. (12) Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. (13) Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. (14) Department of Pulmonary Disease, Leiden University Medical Center, Leiden, The Netherlands. (15) Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (16) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (17) Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. (18) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. shvdburg@lumc.nl.
