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Arginase-1 targeting peptide vaccine in patients with metastatic solid tumors - A phase I trial
Cathrine Lund Lorentzen1, Evelina Martinenaite1,2, Julie Westerlin Kjeldsen1
1National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Background:
Arginase-1-producing cells inhibit T cell-mediated anti-tumor responses by reducing L-arginine levels in the tumor microenvironment. T cell-facilitated elimination of arginase-1-expressing cells could potentially restore L-arginine levels and improve anti-tumor responses. The activation of arginase-1-specific T cells may convert the immunosuppressive tumor microenvironment and induce or strengthen local Th1 inflammation. In the current clinical study, we examined the safety and immunogenicity of arginase-1-based peptide vaccination.
Methods:
In this clinical phase I trial, ten patients with treatment-refractory progressive solid tumors were treated. The patients received an arginase-1 peptide vaccine comprising three 20-mer peptides from the ARG1 immunological "hot spot" region in combination with the adjuvant Montanide ISA-51. The vaccines were administered subcutaneously every third week (maximum 16 vaccines). The primary endpoint was to evaluate safety assessed by Common Terminology Criteria for Adverse Events 4.0 and laboratory monitoring. Vaccine-specific immune responses were evaluated using enzyme-linked immune absorbent spot assays and intracellular cytokine staining on peripheral blood mononuclear cells. Clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors 1.1.
Results:
The vaccination was feasible, and no vaccine-related grade 3-4 adverse events were registered. Nine (90%) of ten patients exhibited peptide-specific immune responses in peripheral blood mononuclear cells. Six (86%) of the seven evaluable patients developed a reactive T cell response against at least one of the ARG1 peptides during treatment. A phenotypic classification revealed that arginase-1 vaccine-specific T cells were both CD4+ T cells and CD8+ T cells. Two (20%) of ten patients obtained stable disease for respectively four- and seven months on vaccination treatment.
Conclusion:
The peptide vaccine against arginase-1 was safe. Nine (90%) of ten patients had measurable peptide-specific responses in the periphery blood, and two (20%) of ten patients attained stable disease on protocol treatment.
Clinical Trial Registration:
https://clinicaltrials.gov/ct2/show/NCT03689192, identifier NCT03689192.
Insights
This study shows that an arginase-1 peptide vaccine is safe and can generate immune responses in patients with solid tumors. The vaccine led to stable disease in 20% of patients, indicating potential for improving anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Arginase-1-producing cells create an immunosuppressive tumor microenvironment by depleting L-arginine.
- Eliminating arginase-1-expressing cells can restore L-arginine levels and enhance anti-tumor immunity.
- Activating arginase-1-specific T cells may reverse tumor immunosuppression and promote Th1 inflammation.
Purpose of the Study:
- To assess the safety and immunogenicity of a novel arginase-1 peptide vaccine.
- To evaluate the vaccine's impact on T cell responses in patients with advanced solid tumors.
Main Methods:
- A Phase I clinical trial involving ten patients with treatment-refractory solid tumors.
- Administration of an arginase-1 peptide vaccine with Montanide ISA-51 adjuvant subcutaneously.
- Monitoring of safety via Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and assessment of immune responses using ELISPOT and intracellular cytokine staining.
Main Results:
- The arginase-1 peptide vaccine was safe and feasible, with no grade 3-4 treatment-related adverse events.
- 90% of patients demonstrated peptide-specific immune responses in peripheral blood mononuclear cells.
- 20% of patients achieved stable disease for 4 and 7 months, respectively.
Conclusions:
- The arginase-1 peptide vaccine is safe and elicits measurable peptide-specific immune responses.
- The vaccine demonstrated potential clinical benefit by inducing stable disease in a subset of patients.
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