Follicular lymphoma: Nature Reviews. Disease Primers

Chimeric antigen receptor (CAR)-T cell therapies have improved the outcome for many patients with relapsed or refractory aggressive B-cell lymphomas. In 2017, axicabtagene ciloleucel and soon after tisagenlecleucel became the first approved CAR-T cell products for patients with high-grade B-cell lymphomas or diffuse large B-cell lymphoma (DLBCL) who are relapsed or refractory to ≥ 2 prior lines of therapy; lisocabtagene maraleucel was approved in 2021. Safety and efficacy outcomes from the pivotal trials of each CAR-T cell therapy have been reported. Despite addressing a common unmet need in the large B-cell lymphoma population and utilizing similar CAR technologies, there are differences between CAR-T cell products in manufacturing, pivotal clinical trial designs, and data reporting. Early reports of commercial use of axicabtagene ciloleucel and tisagenlecleucel provide the first opportunities to validate the impact of patient characteristics on the efficacy and safety of these CAR-T cell therapies in the real world. Going forward, caring for patients after CAR-T cell therapy will require strategies to monitor patients for sustained responses and potential long-term side effects. In this review, product attributes, protocol designs, and clinical outcomes of the key clinical trials are presented. We discuss recent data on patient characteristics, efficacy, and safety of patients treated with axicabtagene ciloleucel or tisagenlecleucel in the real world. Finally, we discuss postinfusion management and preview upcoming clinical trials of CAR-T cell therapies.

Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials.

As a widely recognized standard regimen, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is able to cure two-thirds patients with diffuse large B cell lymphoma (DLBCL), and the remaining patients suffer from refractory or relapsed disease due to resistance to R-CHOP and fare poorly. Unsatisfied outcomes for those relapsed/refractory patients prompted efforts to discover new treatment approaches for DLBCL, including chimeric antigen receptor T cells, bispecific T cell engagers, immunomodulatory drugs, immune checkpoint inhibitors, monoclonal antibodies, antibody–drug conjugates, molecular pathway inhibitors, and epigenetic-modifying drugs. Herein, up-to-date data about the most promising treatment approaches for DLBCL are recapitulated, and novel genetic classification systems are introduced to guide individualized treatment for DLBCL.

/pdf/new-agents-and-regimens-for-diffuse-large-b-cell-lymphoma-4953m0025l.pdf

New agents and regimens for diffuse large B cell lymphoma

T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized. Here, we introduce a class of bispecific antibodies that mimic signal 2 by bridging TSA to the costimulatory CD28 receptor on T cells. We term these TSAxCD28 bispecifics and describe two such bispecific antibodies: one specific for ovarian and the other for prostate cancer antigens. Unlike CD28 superagonists, which broadly activate T cells and resulted in profound toxicity in early clinical trials, these TSAxCD28 bispecifics show limited activity and no toxicity when used alone in genetically humanized immunocompetent mouse models or in primates. However, when combined with TSAxCD3 bispecifics, they enhance the artificial synapse between a T cell and its target cell, potentiate T cell activation, and markedly improve antitumor activity of CD3 bispecifics in a variety of xenogeneic and syngeneic tumor models. Combining this class of CD28-costimulatory bispecific antibodies with the emerging class of TSAxCD3 bispecifics may provide well-tolerated, off-the-shelf antibody therapies with robust antitumor efficacy.

A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies.

Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of B- and T-lymphocytes in circulation, lymphoid tissues, and tumor. The model was developed and validated using mosunetuzumab nonclinical and blinatumomab clinical data. Simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response. These results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses.

/pdf/mitigating-the-risk-of-cytokine-release-syndrome-in-a-phase-4z0yp7ww3d.pdf

Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling

Mosunetuzumab, a Full-Length Bispecific CD20/CD3 Antibody, Displays Clinical Activity in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (NHL): Interim Safety and Efficacy Results from a Phase 1 Study

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Scott McClellan

Author Tools

Chat about Author

Papers

Mosunetuzumab, a Full-Length Bispecific CD20/CD3 Antibody, Displays Clinical Activity in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (NHL): Interim Safety and Efficacy Results from a Phase 1 Study