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T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions.

ABSTRACT: Several key advances in the treatment of B-cell non-Hodgkin lymphoma (B-NHL) over the past two decades have strategically exploited B-cell lineage markers suitable for targeting by immunotherapies. First, the addition of the anti-CD20 monoclonal antibody (mAb) rituximab to a range of standard therapies conferred remarkable outcomes improvements in diverse settings, perhaps most prominently an overall survival advantage in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Subsequently, multiple chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have revolutionized the treatment of relapsed/refractory (rel/ref) DLBCL and are active in other B-NHL subtypes as well. Most recently, the longstanding aspiration to exploit patients' endogenous T-cells to combat lymphoma has been achieved via T-cell redirecting therapies such as bispecific antibodies (BsAbs) that incorporate dual targeting of a T-cell antigen such as CD3 plus a B-cell antigen such as CD19 or CD20 expressed by the tumor. These novel agents have demonstrated impressive activity as monotherapies in patients with heavily pre-treated, rel/ref B-NHL of a variety of subtypes. Now, myriad clinical trials are exploring combinations of T-cell redirectors with targeted therapies, antibody-drug conjugates, conventional chemotherapy, and even new immunotherapies. Here, we highlight key landmarks in the development of T-cell redirecting therapies for the treatment of B-NHL, emerging evidence and lessons from recent clinical trials, and exciting new directions in this arena.

SUBMITTER: Russler-Germain DA

PROVIDER: S-EPMC10351267 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions.

Russler-Germain David A DA Ghobadi Armin A

Frontiers in oncology 20230703

Several key advances in the treatment of B-cell non-Hodgkin lymphoma (B-NHL) over the past two decades have strategically exploited B-cell lineage markers suitable for targeting by immunotherapies. First, the addition of the anti-CD20 monoclonal antibody (mAb) rituximab to a range of standard therapies conferred remarkable outcomes improvements in diverse settings, perhaps most prominently an overall survival advantage in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Subsequently, multi ...[more]

PMID: 37465110

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Project description:Non-Hodgkin's lymphoma (NHL) is a cancer that starts in the lymphatic system. In NHL, the important part of the immune system, a type of white blood cells called lymphocytes become cancerous. NHL subtypes include marginal zone lymphoma, small lymphocytic lymphoma, follicular lymphoma (FL), and lymphoplasmacytic lymphoma. The disease can emerge in either aggressive or indolent form. 5-year survival duration after diagnosis is poor among patients with aggressive/relapsing form of NHL. Therefore, it is necessary to understand the molecular mechanisms of pathogenesis involved in NHL establishment and progression. In the next step, we can develop innovative therapies for NHL based on our knowledge in signaling pathways, surface antigens, and tumor milieu of NHL. In the recent few decades, several treatment solutions of NHL mainly based on targeted/directed therapies have been evaluated. These approaches include B-cell receptor (BCR) signaling inhibitors, immunomodulatory agents, monoclonal antibodies (mAbs), epigenetic modulators, Bcl-2 inhibitors, checkpoint inhibitors, and T-cell therapy. In recent years, methods based on T cell immunotherapy have been considered as a novel promising anti-cancer strategy in the treatment of various types of cancers, and particularly in blood cancers. These methods could significantly increase the capacity of the immune system to induce durable anti-cancer responses in patients with chemotherapy-resistant lymphoma. One of the promising therapy methods involved in the triumph of immunotherapy is the chimeric antigen receptor (CAR) T cells with dramatically improved killing activity against tumor cells. The CAR-T cell-based anti-cancer therapy targeting a pan-B-cell marker, CD19 is recently approved by the US Food and Drug Administration (FDA) for the treatment of chemotherapy-resistant B-cell NHL. In this review, we will discuss the structure, molecular mechanisms, results of clinical trials, and the toxicity of CAR-T cell-based therapies. Also, we will criticize the clinical aspects, the treatment considerations, and the challenges and possible drawbacks of the application of CAR-T cells in the treatment of NHL.

Project description:Background: Atypical parkinsonian syndromes are rare, fatal neurodegenerative diseases associated with abnormal protein accumulation in the brain. Examples of these syndromes include progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. A common clinical feature in parkinsonism is a limited improvement with levodopa. So far, there are no disease-modifying treatments to address these conditions, and therapy is only limited to the alleviation of symptoms. Diagnosis is devastating for patients, as prognosis is extremely poor, and the disease tends to progress rapidly. Currently, potential causes and neuropathological mechanisms involved in these diseases are being widely investigated. Objectives: The goal of this review is to summarize recent advances and gather emerging disease-modifying therapies that could slow the progression of atypical parkinsonian syndromes. Methods: PubMed and Google Scholar databases were searched regarding novel perspectives for atypical parkinsonism treatment. The following medical subject headings were used: "atypical parkinsonian syndromes-therapy," "treatment of atypical parkinsonian syndromes," "atypical parkinsonian syndromes-clinical trial," "therapy of tauopathy," "alpha-synucleinopathy treatment," "PSP therapy/treatment," "CBD therapy/treatment," "MSA therapy/treatment," and "atypical parkinsonian syndromes-disease modifying." All search results were manually reviewed prior to inclusion in this review. Results: Neuroinflammation, mitochondrial dysfunction, microglia activation, proteasomal impairment, and oxidative stress play a role in the neurodegenerative process. Ongoing studies and clinical trials target these components in order to suppress toxic protein accumulation. Various approaches such as stem cell therapy, anti-aggregation/anti-phosphorylation agent administration, or usage of active and passive immunization appear to have promising results. Conclusion: Presently, disease-modifying strategies for atypical parkinsonian syndromes are being actively explored, with encouraging preliminary results. This leads to an assumption that developing accurate, safe, and progression-halting treatment is not far off. Nevertheless, the further investigation remains necessary.

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T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions.

Publications

T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions.

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