An immunogenic first-in-human immune modulatory vaccine with PD-L1 and PD-L2 peptides is feasible and shows early signs of efficacy in follicular lymphoma

Klausen, Uffe; Jørgensen, Nicolai Grønne Dahlager; Grauslund, Jacob Handlos; Ahmad, Shamaila Munir; Gang, Anne Ortved; Martinenaite, Evelina; Weis-Banke, Stine Emilie; Breinholt, Marie Fredslund; Novotny, Guy Wayne; Kjeldsen, Julie Westerlin; Holmström, Morten Orebo; Pedersen, Lone Bredo; Poulsen, Christian Bjørn; Hansen, Per Boye; Met, Özcan; Svane, Inge Marie; Niemann, Carsten Utoft; Pedersen, Lars Møller; Andersen, Mads Hald

doi:10.1080/2162402x.2021.1975889

Cited by 4 publications

(14 citation statements)

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“…Being aware of this, we suspected that the poor condition of T cells might be an issue for the vaccine to mount an adequate T-cell immune response. Nonetheless, the vaccines induced T-cell responses similar in frequency and amplitude to responses identified in previous cancer vaccine trials from our institution (19)(20)(21)(22). Hence, overcoming the vast tumor burden might be a greater issue in CLL.…”

Section: Discussionmentioning

confidence: 62%

“…Indurations at the injection site were common and remained during follow-up in some patients. These granulomas are known complications of the use of Montanide and have been reported in earlier vaccine trials with this adjuvant ( 19 , 21 , 22 , 28 ). Two patients experienced chills in close relation to the vaccine, also a known reaction to Montanide ( 28 ).…”

Section: Resultsmentioning

confidence: 76%

“…The vaccine contained 100 µg of a PD-L1-derived peptide (FMTYWHLLNAFTVTVPKDL) and 100 µg of a PD-L2-derived peptide (SLELQLHQIAALFTVTVPKEL) as previously described ( 21 ), both acquired from PolyPeptide Laboratories, Strasbourg, France ( 16 , 25 ). The peptides were dissolved in 500 μl of water with 20% dimethyl sulfoxide (DMSO) and mixed with 500 µl of the adjuvant Montanide ISA-51 (Seppic Inc., Paris, France) immediately before injection, giving a total injection volume of 1 ml.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we successfully activated PD-L1-and PD-L2specific T cells with limited toxicity. Further, we observed some interesting early clinical signals with one patient obtaining a complete response (CR) and additional long-term disease stabilizing effects in several patients, encouraging us to unroll this study in CLL (21). Here, we evaluated the efficacy and safety of the PD-L1 and PD-L2 vaccines in treatment-naïve CLL patients with unmutated IgHV.…”

Section: Introductionmentioning

confidence: 99%

“…Such anti-Tregs can also recognize PD-L1 and PD-L2 and can directly react toward both malignant and non-malignant cells expressing these epitopes ( 14 – 17 ). The anti-Tregs can be mobilized by target-specific peptide vaccines, and their anti-cancer effect has been explored in several malignancies ( 18 – 21 ). Noteworthy is the recent results from a phase 1/2 vaccination study combining PD-L1 and indoleamine-2,3-dioxygenase (IDO)-derived peptides in combination with the anti-PD-1 monoclonal antibody nivolumab in patients with malignant melanoma ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV

et al. 2022

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Chronic lymphocytic leukemia (CLL) patients with unmutated immunoglobulin heavy chain (IgHV) are at risk of early disease progression compared to patients with mutated IgHV. As a preventive strategy, we treated 19 previously untreated CLL patients with unmutated IgHV in a phase 1/2 trial (clinicaltrials.gov, NCT03939234) exploring the efficacy and toxicity of a therapeutic cancer vaccine containing peptides derived from programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2), hoping to restore immunological control of the disease. According to the International Workshop on Chronic lymphocytic Leukemia (iwCLL) response criteria, no patients obtained a response; however, during follow-up, one patient had complete normalization of the peripheral lymphocyte count and remained in biochemical remission after a follow-up time of 15 months. At the end of treatment, one patient had progressed, and 17 patients had stable disease. During follow-up with a median time of 23.5 months since inclusion, seven patients had progressed, and eight patients had stable disease. The median time to first treatment (TTFT) from diagnosis was 90.3 months with a median follow-up time of 50.1 months. This apparent favorable outcome in TTFT needs to be investigated in a randomized setting, as our population may have been biased. More than 80% of patients obtained vaccine-specific immune responses, confirming the immunogenicity of the vaccine. The vaccine was generally well tolerated with only grade I–II adverse events. Although there were some signs of clinical effects, the vaccine seems to be insufficient as monotherapy in CLL, possibly due to a high tumor burden. The efficacy of the vaccine should preferably be tested in combination with novel targeted therapies or as a consolidating treatment.

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Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV

et al. 2022

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Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab

Lorentzen¹,

Kjeldsen²,

Ehrnrooth³

et al. 2023

J Immunother Cancer

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BackgroundWe have previously published initial efficacy of the indoleamine 2,3-dioxygenase (IDO)/anti-programmed death ligand 1 (PD-L1) vaccine in combination with nivolumab in 30 anti-PD-1 therapy naïve patients with metastatic melanoma (cohort A). We now report long-term follow-up of patients in cohort A. Further, we report results from cohort B, where the peptide vaccine was added to anti-PD-1 therapy for patients with progressive disease during anti-PD-1 treatment.MethodsAll patients were treated with a therapeutic peptide vaccine in Montanide targeting IDO and PD-L1 combined with nivolumab (NCT03047928). A long-term follow-up of safety, response rates, and survival rates were performed in cohort A including patient subgroup analyses. Safety and clinical responses were analyzed for cohort B.ResultsCohort A: At data cut-off, January 5, 2023, the overall response rate (ORR) was 80%, and 50% of the 30 patients obtained a complete response (CR). The median progression-free survival (mPFS) was 25.5 months (95% CI 8.8 to 39), and median overall survival (mOS) was not reached (NR) (95% CI 36.4 to NR). The minimum follow-up time was 29.8 months, and the median follow-up was 45.3 months (IQR 34.8–59.2). A subgroup evaluation further revealed that cohort A patients with unfavorable baseline characteristics, including either PD-L1 negative tumors (n=13), elevated lactate dehydrogenase (LDH) levels (n=11), or M1c (n=17) obtained both favorable response rates and durable responses. The ORR was 61.5%, 79%, and 88% for patients with PD-L1−tumors, elevated LDH, and M1c, respectively. The mPFS was 7.1 months for patients with PD-L1−tumors, 30.9 months for patients with elevated LDH, and 27.9 months for M1c patients. Cohort B: At data cut-off, the best overall response was stable disease for 2 of the 10 evaluable patients. The mPFS was 2.4 months (95% CI 1.38 to 2.52), and the mOS was 16.7 months (95% CI 4.13 to NR).ConclusionThis long-term follow-up confirms the promising and durable responses in cohort A. Subgroup analyses of patients with unfavorable baseline characteristics revealed that high response rates and survival rates were also found in patients with either PD-L1 negative tumors, elevated LDH levels, or M1c. No meaningful clinical effect was demonstrated in cohort B patients.Trial registration numberNCT03047928.

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An arginase1- and PD-L1-derived peptide-based vaccine for myeloproliferative neoplasms: A first-in-man clinical trial

et al. 2023

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IntroductionArginase-1 (ARG1) and Programed death ligand-1 (PD-L1) play a vital role in immunosuppression in myeloproliferative neoplasms (MPNs) and directly inhibit T-cell activation and proliferation. We previously identified spontaneous T-cell responses towards PD-L1 and ARG1 derived peptide epitopes in patients with MPNs. In the present First-in-Man study we tested dual vaccinations of ARG1- derived and PD-L1-derived peptides, combined with Montanide ISA-51 as adjuvant, in patients with Janus Kinase 2 (JAK2) V617F-mutated MPN.MethodsSafety and efficacy of vaccination with ARG1- derived and PD-L1-derived peptides with montanide as an adjuvant was tested in 9 patients with MPN The primary end point was safety and toxicity evaluation. The secondary end point was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT04051307).ResultsThe study included 9 patients with JAK2-mutant MPN of which 8 received all 24 planned vaccines within a 9-month treatment period. Patients reported only grade 1 and 2 vaccine related adverse events. No alterations in peripheral blood counts were identified, and serial measurements of the JAK2V617F allelic burden showed that none of the patients achieved a molecular response during the treatment period. The vaccines induced strong immune responses against both ARG1 and PD-L1- derived epitopes in the peripheral blood of all patients, and vaccine-specific skin-infiltrating lymphocytes from 5/6 patients could be expanded in vitro after a delayed-type hypersensitivity test. In two patients we also detected both ARG1- and PD-L1-specific T cells in bone marrow samples at the end of trial. Intracellular cytokine staining revealed IFNγ and TNFγ producing CD4+- and CD8+- T cells specific against both vaccine epitopes. Throughout the study, the peripheral CD8/CD4 ratio increased significantly, and the CD8+ TEMRA subpopulation was enlarged. We also identified a significant decrease in PD-L1 mRNA expression in CD14+ myeloid cells in the peripheral blood in all treated patients and a decrease in ARG1 mRNA expression in bone marrow of 6 out of 7 evaluated patients.ConclusionOverall, the ARG1- and PD-L1-derived vaccines were safe and tolerable and induced strong T-cell responses in all patients. These results warrant further studies of the vaccine in other settings or in combination with additional immune-activating treatments.

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An immunogenic first-in-human immune modulatory vaccine with PD-L1 and PD-L2 peptides is feasible and shows early signs of efficacy in follicular lymphoma

Cited by 4 publications

References 48 publications

Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV

Anti-PD-L1/PD-L2 therapeutic vaccination in untreated chronic lymphocytic leukemia patients with unmutated IgHV

Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab

An arginase1- and PD-L1-derived peptide-based vaccine for myeloproliferative neoplasms: A first-in-man clinical trial

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