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

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.

Therapeutic Cancer Vaccination With a Peptide Derived From the Calreticulin Exon 9 Mutations Induces Strong Cellular Immune Responses in Patients With CALR-Mutant Chronic Myeloproliferative Neoplasms.

BACKGROUND: The calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR-mutant MPN. METHODS: The safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALRmut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446). RESULTS: Patients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines. CONCLUSION: Therapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response.

Vaccination against PD-L1 with IO103 a Novel Immune Modulatory Vaccine in Basal Cell Carcinoma: A Phase IIa Study.

Antitumor activity of immune checkpoint blocking antibodies against programmed death 1 (PD-1) in basal cell carcinoma (BCC) has been described. IO103 is a peptide vaccine against the major PD-1 ligand PD-L1. A phase IIa study of vaccination with IO103 and Montanide adjuvant was conducted in patients with resectable BCC (NCT03714529). Vaccinations were given six times every 2 weeks (q2w), followed by three vaccines q4w in responders. Primary endpoints were clinical responses of target tumors, change in target tumor size and immune responses to the vaccine. Secondary endpoint was safety. One tumor per patient was designated target tumor and biopsied twice during the course of vaccination. Synchronous non-target BCCs were not biopsied during vaccinations. Ten patients were vaccinated (six patients received six vaccinations and four patients received nine vaccinations). A partial response (PR) was seen in two target tumors. Two complete responses (CR) and one PR were observed in eight non-target tumors in four patients. No tumors progressed. Related adverse events were grade 1 and reversible. Immune responses against IO103 were induced in blood samples from nine of ten and skin-infiltrating lymphocytes from five of the nine patients. The regressions seen in non-target tumors suggest that IO103 may be effective against a subtype of BCC.

Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial.

Background: Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793). Methods: Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described. Results: All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations. Conclusion: Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy. Clinical Trial Registration: clinicaltrials.org, identifier NCT03042793.

[Therapeutic cancer vaccination for treatment of haematological cancers].

Few trials testing the clinical efficacy of therapeutic cancer vaccination have been successful, and therapeutic cancer vaccines are yet to enter the clinic for treatment of haematological cancers. The review summarises the present knowledge of the interplay between cancer and the immune system. These novel insights have uncovered knowledge, which can be used to enhance the effect of therapeutic cancer vaccines in haematology. Immune checkpoint inhibitors, immunomodulating agents, radiotherapy and vaccination against regulatory mechanisms can potentially increase the clinical effect of cancer vaccines for haematological cancer.

[Cancer immune therapy for the treatment of haematological malignancies].

Cancer immune therapy is now used routinely for the treatment of several solid malignancies, albeit just recently having entered the clinic for treatment of haematological malignancies. Several studies demonstrate that cancer immune therapy is a promising treatment modality for the latter. Especially treatment with chimeric antigen receptor T cells for acute lymphoblastic leukaemia and lymphoma is promising. Other promising treatment modalities are immune check point inhibitors for both lymphoid and myeloid malignancies, as well as therapeutic cancer vaccination targeting tumour antigens.

Cancer immune therapy for lymphoid malignancies: recent advances.

Immunotherapy has played an important part in improving the life of patients with lymphoproliferative diseases especially since the addition of rituximab to chemotherapy in the CD20-positive neoplasms in the 1990s. While this field of passive immunotherapy is continuously evolving, several breakthroughs will expand the treatment modalities to include more active immunotherapy. With the approval of immune checkpoint-blocking antibodies for Hodgkin lymphoma and bispecific antibodies for acute lymphoblastic leukemia (ALL), activation of endogenous T cells already plays a role in several lymphoid malignancies. With the approval of cellular therapies with CAR-T cells for ALL and diffuse large B cell lymphoma, the impact of the manipulation of immune responses is taken even further. Vaccines are cellular therapies in the opposite end of the spectrum in terms of side effects, and while the big breakthrough is still to come, the prospect of a very low-toxic immunotherapy which could be applicable also in premalignant states or in frail patients drives a considerable research activity in the area. In this review, we summarize the mechanisms of action and clinical data on trials in the lymphoid neoplasms with chimeric antigen receptor T cells, bispecific antibodies, immune checkpoint-blocking antibodies, and antineoplastic vaccination therapy.

Novel Strategies for Peptide-Based Vaccines in Hematological Malignancies.

Peptides vaccination is an interesting approach to activate T-cells toward desired antigens in hematological malignancies. In addition to classical tumor associated antigens, such as cancer testis antigens, new potential targets for peptide vaccination comprise neo-antigens including JAK2 and CALR mutations, and antigens from immune regulatory proteins in the tumor microenvironment such as programmed death 1 ligands (PD-L1 and PD-L2). Immunosuppressive defenses of tumors are an important challenge to overcome and the T cell suppressive ligands PD-L1 and PD-L2 are often present in tumor microenvironments. Thus, PD-L1 and PD-L2 are interesting targets for peptide vaccines in diseases where the tumor microenvironment is known to play an essential role such as multiple myeloma and follicular lymphoma. In myelodysplastic syndromes the drug azacitidine re-exposes tumor associated antigens, why vaccination with related peptides would be an interesting addition. In myeloproliferative neoplasms the JAK2 and CALR mutations has proven to be immunogenic neo-antigens and thus possible targets for peptide vaccination. In this mini review we summarize the basis for these novel approaches, which has led to the initiation of clinical trials with various peptide vaccines in myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and follicular lymphoma.

Peptide vaccination against multiple myeloma using peptides derived from anti-apoptotic proteins: a phase I trial.

The B-cell lymphoma-2 (Bcl-2) family of proteins play a crucial role in multiple myeloma (MM), contributing to lacking apoptosis which is a hallmark of the disease. This makes the Bcl-2 proteins interesting targets for therapeutic peptide vaccination. We report a phase I trial of therapeutic vaccination with peptides from the proteins Bcl-2, Bcl-XL and Mcl-1 in patients with relapsed MM. Vaccines were given concomitant with bortezomib. Out of 7 enrolled patients, 4 received the full course of 8 vaccinations. The remaining 3 patients received fewer vaccinations due to progression, clinical decision of lacking effect and development of hypercalcemia, respectively. There were no signs of toxicity other than what was to be expected from bortezomib. Immune responses to the peptides were seen in all 6 patients receiving more than 2 vaccinations. Three patients had increased immune responses after vaccination. Vaccination against Bcl-2 was well tolerated and was able to induce immune responses in patients with relapsed MM.