# Editorial: Innovative immunotherapy strategies for enhanced treatment of Hodgkin and non-Hodgkin lymphomas

Michael J Robertson, Eric Vivier, Penny Fang

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Michael J Robertson, Eric Vivier, Penny Fang. Editorial: Innovative immunotherapy strategies for enhanced treatment of Hodgkin and non-Hodgkin lymphomas. Frontiers in Immunology, 2025, 16, 10.3389/fimmu.2025.1642505. [hal-05505663](https://hal HAL Id: [hal-05505663](https://wwwHAL.fr/hal-05505663))

Submitted on 11 Feb 2026

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OPEN ACCESS

EDITED AND REVIEWED BY
Peter Brossart,
University of Bonn, Germany

*CORRESPONDENCE
Michael J. Robertson

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mjrobert@iu.edu

RECEIVED 06 June 2025

ACCEPTED 10 June 2025

PUBLISHED 20 June 2025

CITATION

Robertson MJ, Vivier E and Fang P (2025) Editorial: Innovative immunotherapy strategies for enhanced treatment of Hodgkin and non-Hodgkin lymphomas. *Front. Immunol.* 16:1642505. doi: 10.3389/fimmu.2025.1642505

COPYRIGHT

© 2025 Robertson, Vivier and Fang. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Editorial: Innovative immunotherapy strategies for enhanced treatment of Hodgkin and non-Hodgkin lymphomas

Michael J. Robertson<fnref n="1" />*, Eric Vivier<fnref n="2" /> and Penny Fang³

KEYWORDS

lymphoma, immunotherapy, CAR (chimeric antigen receptor) T-cell therapy, immune checkpoint inhibitors, monoclonal Abs

## Editorial on the Research Topic

### Innovative immunotherapy strategies for enhanced treatment of Hodgkin and non-Hodgkin lymphomas

Immunotherapy is a major component of current cancer treatment. Rituximab, one of the first efficacious immunotherapies for cancer, remains integral to treatment regimens for B cell lymphomas. Recent advances include approval of CD19-directed chimeric antigen receptor (CAR) T-cell therapies and CD20 x CD3 bispecific antibodies for relapsed and refractory B cell lymphomas (1, 2). Furthermore, immune checkpoint inhibitors (ICI) and CD30 antibody-drug conjugates have significantly improved treatment outcomes for classic Hodgkin lymphoma (cHL) (2). However clinical results remain suboptimal and further improvement in therapeutic options is needed. The seven original research articles, two case reports, and review article in this Research Project survey promising novel strategies for treatment of lymphoma.

Several articles investigate new approaches for CAR T-cell therapy. Efficacy of CAR T-cell therapy could be enhanced by use of CAR T-cells directed at more than one target antigen (3). Huang et al. and Luo et al. describe the safety and efficacy of dual CD20/CD30- and CD19/CD22-directed autologous CAR T-cells for treatment of aggressive B cell lymphomas. The patient in the report of Huang et al. had diffuse large B cell lymphoma (DLBCL) that had transformed from low-grade follicular lymphoma. The patient had durable complete response after CD20/CD30-directed CAR T-cell therapy even though the malignant cells expressed CD30 only weakly and partially. CD30 antibody-drug conjugate brentuximab vedotin has significant activity in DLBCL irrespective of CD30 expression (4). CD30 could be expressed by tumor cells at levels below the limit of detection by routine immunohistochemistry but sufficient to mediate antitumor activity. CD30-targeted agents could also affect tumor cells indirectly by modifying the tumor microenvironment. The patient did not experience cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).

Luo et al. took a sequential approach to treat a patient with refractory Burkitt lymphoma. High-dose chemotherapy and autologous peripheral blood stem cell

<footnote n="1">¹Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States,</footnote>

<footnote n="2">²Centre d'Immunologie de Marseille-Luminy, Marseille, France, ³Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States</footnote>
transplantation was done to reduce tumor bulk and as
lymphodepletion, followed by infusion of CD19/CD22-directed
CAR T-cells. Maintenance treatment with anti-PD-1 antibody
tislelizumab was given after the patient achieved complete
response. In addition to employing a dual targeting extracellular
domain, the third generation CAR used in this study had a novel
intracellular signaling domain that included a CD3 zeta motif and
costimulatory elements of CD28 and TLR2.

After apheresis has been done to collect autologous lymphocytes, bridging therapy is often needed to prevent rapid disease progression while awaiting production of CAR T-cells (5). Radiotherapy may offer advantages compared to chemotherapy for bridging therapy (5, 6). Ruan et al. have investigated the feasibility and potential mechanism of action of hyper-fractionated radiotherapy as bridging treatment prior to CD19-directed CAR T-cell therapy. Hyper-fractionated radiotherapy was safe and effective and, within limitations of an uncontrolled study, did not appear to affect incidence of CRS or ICANS. Exploratory studies suggested that bridging radiotherapy may have immunomodulatory effects.

Non-viral gene transfer techniques have been explored as an
alternative to retroviral or lentiviral vectors for production of CAR
T-cells. Transposon DNA plasmids (such as Sleeping Beauty and
piggyBac) have significant advantages, including reduced
production costs and immunogenicity compared to viral vectors,
but are limited by lower transduction efficiency (7). Mucha et al.
describe a novel procedure for non-viral production of CAR T-cells
involving piggyBac transposons and irradiated allogeneic feeder
cells. This approach allowed large scale production of clinical grade
CD19-directed autologous CAR T-cells that were used successfully
in clinical trials.

ICI have shown impressive activity for treatment of cHL and
primary mediastinal large B cell lymphoma, but efficacy of ICI for
most other types of non-Hodgkin lymphoma has been limited.
Ricard et al. studied ICI-based treatment of angioimmunoblastic T-
cell lymphoma (AITCL). The tumor microenvironment of AITCL
often contains EBV-infected immunoblasts that promote
overexpression of PD-L1 (8). Furthermore, mutations in genes
regulating DNA methylation, including TET2 and DNMT3A, are
seen in peripheral T cell lymphomas, including AITCL (8, 9).
Therefore Ricard et al. used hypomethylating agent 5-azacytidine
together with ICI nivolumab to treat patients with AITCL.
Treatment was well tolerated and overall response rate was 78%.

Ruggeri et al. examined expression of serine/threonine kinase CK2 in cHL. CK2α was overexpressed in cHL cell lines and Reed-Sternberg cells of patients with cHL. Silmitasertib, an inhibitor of CK2α, caused apoptosis of cHL cell lines and decreased expression of PD-L1. Thus CK2α may be a target for innovative therapies of cHL.

Rituximab, a type I chimeric CD20 monoclonal antibody (mAb) of IgG1 isotype, has revolutionized the treatment of B cell lymphomas. The mechanism of action of rituximab is complex and may involve antibody-dependent cellular phagocytosis (ADCP) by monocytes and macrophages, antibody-dependent cellular cytotoxicity by NK cells, and complement-dependent cytotoxicity. Nguyen et al. show that a CD20 mAb of IgG2 isotype (rituximab-IgG2) can enhance ADCP induced by different isotypes of

rituximab and other therapeutic mAb. Rituximab-IgG2 augments
ADCP in part by causing downregulation of CD47 on lymphoma
cells. Rituximab-IgG2 also induced more apoptosis of lymphoma
cells than rituximab-IgG1 or rituximab-IgG3.

Fan et al. investigated the causal relationship between
metabolites, immune cell phenotypes, and risk of lymphoma and
chronic lymphocytic leukemia (CLL) in Mendelian randomization
analysis. Several metabolites and immune cell phenotypes were
associated with different subtypes of lymphoma. However, evidence
that immune cell phenotype was responsible for the effect of
metabolites on risk of lymphoma was found only for DLBCL
and CLL.

Wang et al. conducted a retrospective study of clinical
characteristics of marginal zone lymphoma (MZL) and its
response to treatment in the era of immunotherapy. MZL is a
low-grade B cell lymphoma with three subtypes: extranodal MZL of
mucosa-associated lymphoid tissue (MALT lymphoma), nodal
MZL, and splenic MZL (10). Among 265 newly diagnosed
patients with MZL reported by Wang et al., 66% had MALT
lymphoma and the remaining cases were about equally
distributed between nodal and splenic MZL. Overall response
rates did not differ between patients receiving rituximab plus
chemotherapy versus obinutuzumab plus chemotherapy.
However, in a subgroup analysis of 51 patients with high tumor
burden the overall response rate favored obinutuzumab over
rituximab. This observation requires confirmation in prospective
studies with larger numbers of patients that have high
tumor burden.

Primary large B cell lymphomas of immune-privileged sites
include primary DLBCL of the central nervous system (PCNSL),
primary vitreoretinal DLBCL (PVRL), and primary testicular
DLBCL (PTL). These aggressive lymphomas were grouped
together in the 5th Edition of the World Health Organization
Classification of Lymphoid Neoplasms based on their common
biological features (11). Wang et al. have reviewed the
epidemiology, pathogenesis, prognosis, and therapy of PCNSL,
PVRL, and PTL. They discuss several novel therapeutic
approaches involving small molecule inhibitors, antibody-drug
conjugates, bispecific antibodies, and CAR-T cells for treatment
of these challenging diseases. Finally, one should also consider the
development of Natural Killer cell engagers which are in clinical
trial in non-Hodgkin B cell lymphomas (12).

Author contributions

MR: Writing – review & editing, Writing – original draft. EV:
Writing – review & editing. PF: Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

## Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

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4. Bartlett NL, Hahn U, Kim W-S, Fleury I, Laribi K, Bergua J-M, et al. Brentuximab vedotin combination for relapsed diffuse large B-cell lymphoma. *J Clin Oncol.* (2025) 43:1061-72. doi: 10.1200/JCO-24-02242

5. Pinnix CC, Gunther JR, Dabaja BS, Strati P, Fang P, Hawkins MC, et al. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. *Blood Adv.* (2020). doi: 10.1182/bloodadvances.2020001837

6. Saifi O, Lester SC, Breen WG, Rule WG, Lin Y, Bennani NN, et al. Incorporating radiation with anti-CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory non-Hodgkin lymphoma: a multicenter consensus approach. *Am J Hematol.* (2024) 99:124-34. doi: 10.1002/ajh.27155

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