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Immunopeptidomics-Guided Warehouse Design for Peptide-Based Immunotherapy in Chronic Lymphocytic Leukemia.

ABSTRACT: Antigen-specific immunotherapies, in particular peptide vaccines, depend on the recognition of naturally presented antigens derived from mutated and unmutated gene products on human leukocyte antigens, and represent a promising low-side-effect concept for cancer treatment. So far, the broad application of peptide vaccines in cancer patients is hampered by challenges of time- and cost-intensive personalized vaccine design, and the lack of neoepitopes from tumor-specific mutations, especially in low-mutational burden malignancies. In this study, we developed an immunopeptidome-guided workflow for the design of tumor-associated off-the-shelf peptide warehouses for broadly applicable personalized therapeutics. Comparative mass spectrometry-based immunopeptidome analyses of primary chronic lymphocytic leukemia (CLL) samples, as representative example of low-mutational burden tumor entities, and a dataset of benign tissue samples enabled the identification of high-frequent non-mutated CLL-associated antigens. These antigens were further shown to be recognized by pre-existing and de novo induced T cells in CLL patients and healthy volunteers, and were evaluated as pre-manufactured warehouse for the construction of personalized multi-peptide vaccines in a first clinical trial for CLL (NCT04688385). This workflow for the design of peptide warehouses is easily transferable to other tumor entities and can provide the foundation for the development of broad personalized T cell-based immunotherapy approaches.

SUBMITTER: Nelde A

PROVIDER: S-EPMC8297687 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Immunopeptidomics-guided warehouse design for peptide-based immunotherapy in chronic lymphocytic leukemia

Project description:In recent years the clinical success of T cell-based immunotherapy approaches has revolutionized treatment of solid tumors and hematological malignancies. However, still some patients do not respond to available therapies at all, others for limited time only. A promising low side-effect approach is peptide-based immunotherapy, which relies on specific immune recognition of tumor-associated human leucocyte antigen (HLA)-presented peptides. In this study, we developed a workflow for the immunopeptidome-guided design of off-the shelf warehouses for personalized peptide vaccines using the example of chronic lymphocyte leukemia (CLL). The so defined warehouses could provide the basis for different T cell-based immunotherapy approaches such as TCR-engineered T cell transfer or multi-peptide vaccinations. The warehouse approach enables a fast and cost-effective way to provide a personalized T cell-based immunotherapeutic approach. The here defined peptide warehouse is already utilized for a personalized multi-peptide vaccine trial (iVAC-XS15-CLL01, NCT04688385).

2021-09-10 | PXD024871 | Pride

Warehouse-based, immunopeptidome-guided design of personalised peptide vaccines shows feasibility in clinical trial evaluation in CLL patients

Project description:Cancer peptide vaccination represents a promising therapeutic approach, but has been hampered by lack of suitable antigens and restricted applicability due to different HLA backgrounds of individual patients. We here introduce a novel warehouse-based concept for composition of personalized peptide vaccines and report on its successful application in a Phase II clinical trial in patients with chronic lymphocytic leukemia (CLL) after first-line therapy. 26 CLL patients in at least partial remission (PR) after 6 months of immuno-chemotherapy were vaccinated with a personalized vaccine compiled from a premanufactured peptide warehouse comprising immunopeptidome-defined CLL-associated peptides. Primary objective was evaluation of immunogenicity, secondary objectives were safety and minimal residual disease (MRD) response. Immunopeptidome-guided vaccine composition was throughout successful, proving the feasibility of warehouse-based vaccine design. Vaccination was well tolerated, with local injection site reactions being the most common adverse event. Only few patients showed vaccine-induced T cell responses, attributable to their inability to mount strong immune responses due to immunechemotherapy and lack of potent adjuvant formulations. Both issues are addressed within a follow-up trial (NCT04688385), combining the immunopeptidome-guided warehouse-based vaccine design reported here with a potent novel adjuvant evaluating personalized multi- peptide vaccination in CLL patients under T cell supportive BTK inhibitor therapies.

2024-11-08 | PXD054248 | Pride

Current state of NK cell-mediated immunotherapy in chronic lymphocytic leukemia.

Project description:Chronic lymphocytic leukemia (CLL) has become one of the most common hematological diseases in western countries, with an annual incidence of 42/100,000. Conventional chemotherapy and targeted therapeutic drugs showed limitations in prognosis or in efficiency in high-risk patients. Immunotherapy represented is one of the most effective therapeutic approaches with the potential of better effect and prognosis. Natural killer (NK) cells are good options for immunotherapy as they can effectively mediate anti-tumor activity of immune system by expressing activating and inhibiting receptors and recognizing specific ligands on various tumor cells. NK cells are critical in the immunotherapy of CLL by enhancing self-mediated antibody-dependent cytotoxicity (ADCC), allogeneic NK cell therapy and chimeric antigen receptor-natural killer (CAR-NK) cell therapy. In this article, we reviewed the features, working mechanisms, and receptors of NK cells, and the available evidence of the advantages and disadvantages of NK cell-based immunotherapies, and put forward future study directions in this field.

| S-EPMC10107371 | biostudies-literature

Exploring a peptide nucleic acid-based antisense approach for CD5 targeting in chronic lymphocytic leukemia.

Project description:We herein report an innovative antisense approach based on Peptide Nucleic Acids (PNAs) to down-modulate CD5 expression levels in chronic lymphocytic leukemia (CLL). Using bioinformatics tools, we selected a 12-mer tract of the CD5 mRNA as the molecular target and synthesized the complementary and control PNA strands bearing a serine phosphate dipeptide tail to enhance their water solubility and bioavailability. The specific recognition of the 12-mer DNA strand, corresponding to the target mRNA sequence by the complementary PNA strand, was confirmed by non-denaturing polyacrylamide gel electrophoresis, thermal difference spectroscopy, circular dichroism (CD), and CD melting studies. Cytofluorimetric assays and real-time PCR analysis demonstrated the downregulation of CD5 expression due to incubation with the anti-CD5 PNA at RNA and protein levels in Jurkat cell line and peripheral blood mononuclear cells from B-CLL patients. Interestingly, we also observed that transfection with the anti-CD5 PNA increases apoptotic response induced by fludarabine in B-CLL cells. The herein reported results suggest that PNAs could represent a potential candidate for the development of antisense therapeutic agents in CLL.

| S-EPMC8970396 | biostudies-literature

Engaging Cytotoxic T and NK Cells for Immunotherapy in Chronic Lymphocytic Leukemia.

Project description:Chronic lymphocytic leukemia (CLL) is characterized by an acquired immune dysfunction. CLL cells affect the phenotype and function of the entire spectrum of innate and adaptive immune cells, including monocytes, T cells, and natural killer (NK) cells, leading to a tumor-supportive environment and reduced immunosurveillance. Novel immunotherapies like immune checkpoint blockade, bi- and tri-specific antibodies, and chimeric antigen receptor (CAR) T cells use the patients' immune system to induce therapeutic responses. Although these novel immunotherapies showed impressive results in several B cell lymphomas, responses in CLL were often disappointing. The strong immunomodulatory effect of CLL is believed to play a pivotal role in the low response rates to these immunotherapeutic strategies. In this review, we summarize how CLL influences the function of non-malignant lymphocytes, with a special focus on T and NK cells, two important cellular mediators for immunotherapy. Secondly, we provide a short overview of the activity of several immunotherapeutics in CLL, and discuss how novel strategies may overcome the disappointing response rates in CLL.

| S-EPMC6747204 | biostudies-literature

Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.

Project description:PurposeNew treatments are needed for patients with fludarabine- and alemtuzumab-refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment; these groups have poor outcomes with available salvage regimens. Ofatumumab (HuMax-CD20) is a human monoclonal antibody targeting a distinct small-loop epitope on the CD20 molecule. We conducted an international clinical study to evaluate the efficacy and safety of ofatumumab in patients with FA-ref and BF-ref CLL.Patients and methodsPatients received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg); response by an independent review committee (1996 National Cancer Institute Working Group criteria) was assessed every 4 weeks until week 24 and then every 3 months until month 24.ResultsThis planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% [corrected] and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. Median progression-free survival and overall survival times were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the BF-ref group, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia.ConclusionOfatumumab is an active, well-tolerated treatment providing clear clinical improvements for fludarabine-refractory patients with very poor-prognosis CLL.

| S-EPMC4979101 | biostudies-literature

Acrocyanosis revealing chronic lymphocytic leukemia.

Project description:Cold agglutinin disease arising in the context of chronic lymphocytic leukemia can misdiagnose a warm autoimmune hemolytic anemia.

| S-EPMC4831394 | biostudies-other

Obinutuzumab in chronic lymphocytic leukemia: design, development and place in therapy.

Project description:For decades, treatment of chronic lymphocytic leukemia (CLL) has been based on chemotherapy. This changed when the first CD20 antibody rituximab was introduced. Since 2008, the combination of chemotherapy and CD20 antibodies has become the standard of care for most patients, and a significant fraction of patients had very long-lasting remissions after chemoimmunotherapy. Despite the improvement of response rates and overall survival (OS) by the use of chemoimmunotherapy, most CLL patients will relapse eventually. One approach to achieve more durable responses was the development of obinutuzumab (GA101), a new type of CD20 antibody that has unique molecular and functional characteristics. Obinutuzumab is a type II fully humanized CD20 antibody that binds to a partly different epitope of the CD20 protein than rituximab and due to its glycoengineered design induces greater antibody-dependent cell-mediated cytotoxicity (ADCC). Initial preclinical observations of a more effective B-cell depletion have been successfully reproduced in clinical trials with CLL patients. This review summarizes results of preclinical as well as clinical studies with obinutuzumab and provides an outlook on its future role in the therapy of CLL.

| S-EPMC5279834 | biostudies-literature

Familial chronic lymphocytic leukemia.

Project description:Purpose of reviewFamilies with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature and strong familial aggregation has been seen in population studies. However, predisposing germline mutations have not been identified. We will discuss the spectrum of conditions associated with CLL in families and the advances in identifying the underlying susceptibility genes.Recent findingsFamilial CLL does not appear to differ substantially from sporadic CLL in terms of prognostic markers and clinical outcome, although it may be associated with more indolent disease. The precursor condition, monoclonal B-cell lymphocytosis, also aggregates in CLL families. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for susceptibility loci but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated several genes as being important in CLL but more studies are needed. Results from whole-genome association studies are promising.SummaryThe ability to conduct large-scale genomic studies in unrelated CLL patients and in high-risk CLL families will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate causal pathways.

| S-EPMC2891437 | biostudies-literature

Potent fluorinated agelastatin analogues for chronic lymphocytic leukemia: design, synthesis, and pharmacokinetic studies.

Project description:Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (-)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure-activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds.

| S-EPMC4079331 | biostudies-literature

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