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

Modi, Dipenkumar; Potugari, Bindu; Uberti, Joseph P.

doi:10.3390/cancers13225827

Cited by 19 publications

(18 citation statements)

References 110 publications

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“…Immunotherapy approaches have played an important role in R/R DLBCL, such as anti-CD47 antibody, bispecific T-cell engager antibody, antibody drug conjugates, and so on, among which CAR-T have the best therapeutic effect (22). A large number of CAR-T-related clinical trials have confirmed the stunning efficacy of CAR-T treatment in R/R DLBCL patients (7).…”

Section: Discussionmentioning

confidence: 99%

Overall survival benefits provided by lenalidomide maintenance after chimeric antigen receptor T cell therapy in patients with refractory/relapsed diffuse large B-cell lymphoma

Ping¹,

Qu²,

Li³

et al. 2022

Ann Transl Med

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Background: Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable effects in refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). However, many patients receiving CAR-T therapy still eventually die of disease recurrence or progression due to target antigen loss or exhaustion of CAR-T cells. Therefore, maintaining the efficacy of CAR-T has become a particular research focus. As lenalidomide can regulate T cell function, we conducted a study to evaluate the efficacy of lenalidomide maintenance after CAR-T therapy in R/R DLBCL patients.Methods: Seven R/R DLBCL patients who received lenalidomide maintenance after CAR-T therapy and nine DLBCL patients that underwent CAR-T treatment alone were included. The clinical data of all subjects were collected to evaluate the efficacy of lenalidomide maintenance. In order to understand the possible mechanisms of lenalidomide in CAR-T therapy, CAR-T copies of peripheral blood were regularly detected by quantitative real-time polymerase chain reaction, and an in vitro test was also conducted.Results: Overall survival (OS) was significantly prolonged in the lenalidomide maintenance group. Furthermore, one case responding to CAR-T therapy initially but suffering a relapse shortly achieved complete remission again after lenalidomide exposure, with an increase in the number of CAR-T copies detected. The in vitro test showed that lenalidomide could delay the exhaustion of CAR-T cells.Conclusions: Lenalidomide maintenance after CAR-T therapy is a safe and effective choice for R/R DLBCL patients. We confirmed that lenalidomide maintenance can improve patients' OS, and the delayed exhaustion of CAR-T cells may contribute to this OS benefit.

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Section: Discussionmentioning

confidence: 99%

Overall survival benefits provided by lenalidomide maintenance after chimeric antigen receptor T cell therapy in patients with refractory/relapsed diffuse large B-cell lymphoma

Ping¹,

Qu²,

Li³

et al. 2022

Ann Transl Med

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“… 114 Since MALT1 inhibition preferentially affects activated, suppressive eTreg cells, patients with the latter group of DLBCL may selectively benefit from Treg cell reprogramming that could synergize with ICT, which has otherwise so far yielded disappointing results in DLBCL. 115 Finally, increased Treg cell infiltration also correlated with an inferior clinical outcome specifically in non-GCB type DLBCL, 116 which primarily represent ABC-type patients with elevated MALT1 protease activation. Thus, particularly in the subset of patients with MALT1-dependent ABC DLBCL, the simultaneous targeting of MALT1 in the tumor as well as in tumor-infiltrating Treg cells may together yield a beneficial clinical response.…”

Section: Opportunities For Simultaneous Cancer Cell-intrinsic and Cel...mentioning

confidence: 99%

Combining precision oncology and immunotherapy by targeting the MALT1 protease

Mempel

Krappmann

2022

J Immunother Cancer

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An innovative strategy for cancer therapy is to combine the inhibition of cancer cell-intrinsic oncogenic signaling with cancer cell-extrinsic immunological activation of the tumor microenvironment (TME). In general, such approaches will focus on two or more distinct molecular targets in the malignant cells and in cells of the surrounding TME. In contrast, the protease Mucosa-associated lymphoid tissue protein 1 (MALT1) represents a candidate to enable such a dual approach by engaging only a single target. Originally identified and now in clinical trials as a lymphoma drug target based on its role in the survival and proliferation of malignant lymphomas addicted to chronic B cell receptor signaling, MALT1 proteolytic activity has recently gained additional attention through reports describing its tumor-promoting roles in several types of non-hematological solid cancer, such as breast cancer and glioblastoma. Besides cancer cells, regulatory T (Treg) cells in the TME are particularly dependent on MALT1 to sustain their immune-suppressive functions, and MALT1 inhibition can selectively reprogram tumor-infiltrating Treg cells into Foxp3-expressing proinflammatory antitumor effector cells. Thereby, MALT1 inhibition induces local inflammation in the TME and synergizes with anti-PD-1 checkpoint blockade to induce antitumor immunity and facilitate tumor control or rejection. This new concept of boosting tumor immunotherapy in solid cancer by MALT1 precision targeting in the TME has now entered clinical evaluation. The dual effects of MALT1 inhibitors on cancer cells and immune cells therefore offer a unique opportunity for combining precision oncology and immunotherapy to simultaneously impair cancer cell growth and neutralize immunosuppression in the TME. Further, MALT1 targeting may provide a proof of concept that modulation of Treg cell function in the TME represents a feasible strategy to augment the efficacy of cancer immunotherapy. Here, we review the role of MALT1 protease in physiological and oncogenic signaling, summarize the landscape of tumor indications for which MALT1 is emerging as a therapeutic target, and consider strategies to increase the chances for safe and successful use of MALT1 inhibitors in cancer therapy.

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“…In NHL patients ( n = 899), PD‐L1 is expressed in DLBCL (31%), marginal zone lymphomas (10%), and follicular lymphoma (5%) 80 . Many monoclonal antibodies are currently available that can be used to treat NHL, including ipilimumab (CTLA‐4 inhibitor), pidilizumab, pembrolizumab (US‐FDA approved), and nivolumab (PD‐1 inhibitors), 81 yet with a questionable effectiveness 82 . The commonly associated AEs of these therapies include fatigue, gastrointestinal‐related AEs, cough, dyspnea, rash, pyrexia, and headache 47,83–85 .…”

Section: Novel Treatments For Nhl and Their Potential Complicationsmentioning

confidence: 99%

The forgotten survivor: A comprehensive review on Non‐Hodgkin lymphoma survivorship

et al. 2022

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The number of non-Hodgkin lymphoma (NHL) survivors is increasing. With the advancement of NHL therapies, it is crucial to focus on the challenges these survivors may face. Three main categories are to be considered in NHL survivorship, including quality of life and uncertainty about the future, possible physical health complications (including cardiovascular disease, infertility, and subsequent neoplasms), and the impact of novel NHL treatments and their potential complications. The latter includes CAR T-cell therapy, monoclonal antibodies, checkpoint inhibitors, and hematopoietic stem cell transplantation. In this report, we aim to shed the light on these aspects and to discuss survivorship care plan for NHL. | INTRODUCTIONIn the United States (US), more than 80 000 patients are diagnosed with non-Hodgkin lymphoma (NHL) annually, 1 and are considered survivors. 2 NHL comprises 4% of all malignancies; however, its impact on survivorship is disproportionate to its incidence due to the higher rates of survival compared with many more common cancers. The American Cancer Society (ACS) predicts that the incidence will rise as people in the U.S. continue to live longer and the risk of NHL increases with age. 1,3 Although this number is expected to proportionally grow with time as more patients are diagnosed and survive with NHL, cancer survivorship care in NHL survivors remains understudied (Figure 1).Cancer survivorship has become an essential part of the cancer care spectrum since formally described in 1986. 4 Many societies and committees are now available to help and guide survivors, their families, and physicians. For instance, the ACS currently has survivorship care guidelines for various solid tumors, including breast, prostate, colorectal, and head and neck cancers. 5 In the field of lymphoma, professional societies are actively developing such guidelines; however, a discrepancy in survivorship care between HL and NHL is observed, favoring HL, despite NHL being more prevalent. This is likely due to From the time of diagnosis onward, NHL patients face several challenges that can impact their physical, mental, and psychosocial wellbeing. 6 A population-based study 7 on 360 NHL patients 5-15 year after diagnosis (82% response rate) assessed their Health-Related Quality of Life (HRQoL) using the 36-item Short-Form Health Survey

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

Cited by 19 publications

References 110 publications

Overall survival benefits provided by lenalidomide maintenance after chimeric antigen receptor T cell therapy in patients with refractory/relapsed diffuse large B-cell lymphoma

Overall survival benefits provided by lenalidomide maintenance after chimeric antigen receptor T cell therapy in patients with refractory/relapsed diffuse large B-cell lymphoma

Combining precision oncology and immunotherapy by targeting the MALT1 protease

The forgotten survivor: A comprehensive review on Non‐Hodgkin lymphoma survivorship

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