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Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions.

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. B-cell receptor (BCR) pathway is essential for malignant B-cell growth, survival, and proliferation. Various immune cells, including T-cells and macrophages in the tumor microenvironment (TME) contribute to tumor cell survival and pathogenesis of chemo-resistance. The presence of many targets on the malignant B-cells and in the TME has led to emergence of novel therapeutic agents. Stem cell transplant is the oldest treatment modality leveraging immune system in DLBCL. Subsequently, CD20 targeting monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy changed the treatment landscape of DLBCL. Recently, multiple novel immunotherapeutic agents have been added in the armamentarium for the management of DLBCL, and many are under development. In this review article, we will review latest updates of immunotherapeutic agents in the management of DLBCL.

SUBMITTER: Modi D

PROVIDER: S-EPMC8616088 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions.

Modi Dipenkumar D Potugari Bindu B Uberti Joseph J

Cancers 20211120 22

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. B-cell receptor (BCR) pathway is essential for malignant B-cell growth, survival, and proliferation. Various immune cells, including T-cells and macrophages in the tumor microenvironment (TME) contribute to tumor cell survival and pathogenesis of chemo-resistance. The presence of many targets on the malignant B-cells and in the TME has led to emergence of novel therapeutic agents. Stem cell transplant is the oldest treatment modal ...[more]

PMID: 34830980

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Project description:Simple Summary There are multiple strategies to target cancer cells, and among the rapidly evolving field is the use of bispecific antibodies and T-cell engagers in the treatment of cancers. These drugs work by recruiting and activating T-cells, a type of white blood cell, to recognize and attack cancer cells. These agents consist of two different antibody fragments: one that binds to a tumor antigen on cancer cells and another that binds to the CD3 receptor on T-cells. Once the T-cell engager binds to both the cancer cell and T-cell, it brings the T-cell into close proximity to the cancer cell, leading to the activation of T-cells and the release of cytokines and cytotoxic molecules that kill the cancer cell. T-cell engagers have shown promising results in the treatment of a variety of hematological malignancies. Research is ongoing to explore their use in the treatment of variety of solid cancers. Nevertheless, T-cell engagers can cause side effects like cytokine release syndrome and neurotoxicity. More research is ongoing to determine their long-term safety and effectiveness. Abstract Monoclonal antibody treatment initially heralded an era of molecularly targeted therapy in oncology and is now widely applied in modulating anti-cancer immunity by targeting programmed cell receptors (PD-1, PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and, more recently, lymphocyte-activation gene 3 (LAG3). Chimeric antigen receptor T-cell therapy (CAR-T) recently proved to be a valid approach to inducing anti-cancer immunity by directly modifying the host’s immune cells. However, such cell-based therapy requires extensive resources such as leukapheresis, ex vivo modification and expansion of cytotoxic T-cells and current Good Manufacturing Practice (cGMP) laboratories and presents significant logistical challenges. Bi-/trispecific antibody technology is a novel pharmaceutical approach to facilitate the engagement of effector immune cells to potentially multiple cancer epitopes, e.g., the recently approved blinatumomab. This opens the opportunity to develop ‘off-the-shelf’ anti-cancer agents that achieve similar and/or complementary anti-cancer effects as those of modified immune cell therapy. The majority of bi-/trispecific antibodies target the tumor-associated antigens (TAA) located on the extracellular surface of cancer cells. The extracellular antigens represent just a small percentage of known TAAs and are often associated with higher toxicities because some of them are expressed on normal cells (off-target toxicity). In contrast, the targeting of intracellular TAAs such as mutant RAS and TP53 may lead to fewer off-target toxicities while still achieving the desired antitumor efficacy (on-target toxicity). Here, we provide a comprehensive review on the emerging field of bi-/tri-specific T-cell engagers and potential therapeutic opportunities.

Project description:Background and objectivePatients with metastatic anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC) often experience years of disease control on targeted therapies but the disease eventually develops resistance and progresses. Multiple clinical trial efforts to incorporate PD-1/PD-L1 immunotherapy into the treatment paradigm for ALK+ NSCLC have resulted in significant toxicities without clear improvement in patient outcomes. Observations from clinical trials, translational studies, and preclinical models suggest the immune system interacts with ALK+ NSCLC and this interaction is heightened with the initiation of targeted therapy. The objective of this review is to summarize knowledge to date about current and potential immunotherapy approaches for patients with ALK+ NSCLC.MethodsTo identify the relevant literature and clinical trials the databases PubMed.gov and ClinicalTrials.gov were queried with keywords "ALK" and "lung cancer". PubMed search was further refined with terms such as "immunotherapy", "tumor microenvironment or TME", "PD-1", and "T cells". The search for clinical trials was limited to interventional studies.Key content and findingsIn this review, the current status of PD-1/PD-L1 immunotherapy for ALK+ NSCLC is updated and alternative immunotherapy approaches are highlighted in the context of available patient level and translational data on the ALK+ NSCLC tumor microenvironment (TME). An increase in CD8+ T cells within the ALK+ NSCLC TME has been observed with targeted therapy initiation across multiple studies. Therapies to augment this including tumor infiltrating lymphocyte (TIL) therapy, modified cytokines, and oncolytic viruses are reviewed. Furthermore, the contribution of innate immune cells in TKI mediated tumor cell clearance is discussed as a future target for novel immunotherapy approaches that promote cancer cell phagocytosis.ConclusionsImmune modulating strategies derived from current and evolving knowledge of the ALK+ NSCLC TME may have a role in ALK+ NSCLC beyond PD-1/PD-L1 based immunotherapy.

Dataset Information

Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions.

Publications

Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions.

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