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TEIPP-vaccination in checkpoint-resistant non-small cell lung cancer: a first-in-human phase I/II dose-escalation
Mitchell Emmers1, Marij J P Welters2, Michelle V Dietz1
1Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
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.
Insights
A novel synthetic long peptide vaccine (TEIPP24) targeting LRPAP1 showed promising safety and immunogenicity in non-small cell lung cancer patients. The vaccine successfully stimulated T-cell immunity, offering a new avenue for cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Loss of the Transporter associated with Antigen Processing (TAP) leads to immunotherapy resistance in cancer.
- Alternative tumor antigens are presented by cancers that escape T-cell therapy.
- LRPAP1 is a novel target antigen for cancer vaccines.
Purpose of the Study:
- To evaluate the safety, tolerability, and immunogenicity of the LRPAP1 synthetic long peptide vaccine (TEIPP24) in a first-in-human study.
- To assess the vaccine's efficacy in HLA-A*0201-positive non-small cell lung cancer (NSCLC) patients progressing after checkpoint blockade.
- To explore the combination of TEIPP24 with PD-1 blockade (pembrolizumab).
Main Methods:
- Multicenter, dose-escalation study with an extension cohort (NCT05898763).
- Patients received TEIPP24 (20, 40, or 100 µg) subcutaneously, with the highest safe dose combined with pembrolizumab in the extension cohort.
- Primary endpoints: safety, tolerability, and immunogenicity; Secondary endpoints: PFS, OS, and tumor response.
Main Results:
- TEIPP24 was well-tolerated in 26 enrolled patients.
- LRPAP1-specific CD8+ T-cell responses were detected in 83% (20/24) of evaluable patients.
- CD4+ T-cell responses were observed in 62% (13/21) of tested patients; combination with pembrolizumab induced activated T-cells.
Conclusions:
- TEIPP24 demonstrates favorable safety and potent immunogenicity in NSCLC patients.
- Vaccine-induced T-cell responses correlated with clinical benefit, including partial response and stable disease.
- TEIPP24 represents a promising therapeutic strategy for advanced NSCLC, particularly in combination with checkpoint inhibitors.
