Can Radiotherapy Be Used With CD20×CD3 Bispecifics in B-Cell Lymphoma?

Bispecific antibodies, and specifically those that target CD20×CD3, have changed treatment for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. Multiple drugs have approvals in the US and in Europe:

• Epcoritamab (Epkinly; Genmab/AbbVie) has accelerated FDA approval as a single agent in diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma after at least 2 lines of therapy; in follicular lymphoma, it has full FDA approval as a single agent after at least 2 lines of therapy and in combination with rituximab and lenalidomide after first relapse.¹
• Glofitamab (Columvi; Genentech) has FDA accelerated approval for heavily pretreated relapsed/refractory DLBCL or LBCL arising from follicular lymphoma; the European Commission granted approval with gemcitabine and oxaliplatin for transplant-ineligible relapsed/refractory DLBCL, following an earlier positive conditional opinion.²
• Mosunetuzumab (Lunsumio; Genentech) has accelerated approval for R/R follicular lymphoma (FL), either by intravenous or subcutaneous administration.³
• Odronextamab under development by Regeneron; does not have US approval, but is approved in Europe for certain patients with both conditions.⁴

But clinicians are sometimes pairing these therapies with radiotherapy (RT), even though the combination has never been formally studied. A new perspective in Cancers reviews what is known. It concludes that the evidence does not yet support practice recommendations.⁵

The authors, from the Radiation Oncology and Hematology units of Azienda Unità Sanitaria Locale–IRCCS di Reggio Emilia in Italy, outline why this question matters. Bispecifics have soared in uptake due to ease of administration.⁵ “These off-the-shelf agents redirect endogenous T cells against CD20-expressing B cells and achieve clinically meaningful response rates without the logistical constraints of cellular therapies,” the authors write. “Even in the pivotal trials, however, the response is neither universal nor durable for most patients.”

In pivotal trials in heavily pretreated R/R DLBCL, overall response rates ranged from 52% to 66%, with complete responses of 36% to 39%. The 12-month progression-free survival (PFS) was 37% with glofitamab, and the median PFS was 4.4 months with epcoritamab.^6,7

RT is a logical partner, the authors write, because lymphomas are among the most radiosensitive cancers. In indolent histologies such as FL, response rates exceed 90% even at low doses. However, low-dose regimens are not expected to produce the same lasting mass reduction in aggressive disease such as DLBCL. And because RT is delivered locally, it avoids the systemic myelosuppression of added chemotherapy, which could deplete the T cells that bispecific antibodies rely on.

The Evidence Base Is Thin

The authors conducted a targeted, non-systematic literature review. The direct evidence consists of (1) 3 case reports, (2) a 7-patient large B-cell lymphoma subgroup, and (3) a 29-patient cohort (Baron et al.) that reported cytokine release syndrome (CRS) and neurotoxicity by agent.⁸ In addition, a 12-patient real-world series added mixed or indirect evidence. All of it comes from case reports or small single-arm, retrospective studies with no comparator arm.

The Baron cohort included patients with DLBCL and FL, most of them treated with mosunetuzumab. The in-field overall response rate was 84% (45% complete response) among 44 evaluable lesions, but this figure also included courses of the CD19×CD3 agent blinatumomab. Among the 24 CD20×CD3 courses, CRS occurred in 25% and immune effector cell–associated neurotoxicity syndrome (ICANS) in 8.3%. These rates are in line with monotherapy trials and showed no apparent link to RT timing or dose. All RT-related toxicities were grade 1 or 2. Because lymphomas respond so readily to radiation, the authors caution that high in-field response rates cannot be read as proof of synergy without a comparator. No study reported survival outcomes tied to RT.

Five Rationales, and Their Evidentiary Status

The authors group the case for the combination into 5 overlapping rationales, all at the hypothesis level. “None of these is an established indication,” the authors note.

Cytoreduction. Baseline tumor bulk is a known risk factor for CRS and ICANS with glofitamab and epcoritamab. In theory, shrinking the tumor with RT before step-up dosing could lower that risk. This is plausible but untested. Two trials of RT with glofitamab in patients with high tumor burden are now studying it: NCT06867536 and the phase 2 Radio-GLO study (NCT07634289).

Modulating the tumor microenvironment. RT can cause local inflammation, improve antigen presentation, and trigger immunogenic cell death and abscopal effects. Any of these could make tumors more susceptible to T-cell engagement. Abscopal-like regressions have been seen after involved-site RT in indolent lymphoma. However, the authors found no direct preclinical evidence that RT boosts CD20×CD3 bispecific activity.

Managing tumor flare reaction. This is the only rationale with direct CD20×CD3 clinical evidence, and that evidence conflicts. In one case, a biopsy confirmed tumor flare rather than true progression, and RT allowed epcoritamab to continue. In another, a patient developed a CRS-compatible fever after RT during late-phase epcoritamab therapy. The fever recurred with each fraction and resolved with IL-6 blockade, which suggests RT may itself provoke inflammation.

Consolidating residual disease. This idea comes from the CAR T literature, where consolidative RT for residual FDG-avid disease has shown encouraging results. No study has tested it after bispecific therapy. The authors also note that residual PET avidity after T-cell–engaging therapy may reflect inflammation or flare rather than viable lymphoma.

Urgent local control during step-up dosing. RT may control threatening disease, independent of immune status, while bispecific antibody doses are being escalated. This rests on clinical judgment and extrapolation rather than data.

The authors stress that RT could also work against bispecifics, by reducing the CD20 target, depleting tumor-infiltrating and circulating T cells, damaging draining lymph structures, promoting immunosuppressive myeloid cells and TGF-β signaling, or selecting for antigen-low resistant clones.

These effects have received far less study, and the authors see "no basis in the current evidence for weighting one direction over the other."

Areas for Future Study

The authors recast common clinical scenarios as open research questions rather than a treatment algorithm:

• Whether RT-induced lymphopenia reduces bispecific efficacy and through which T-cell compartments. Baron et al. found that early post-RT lymphopenia was common but not tied to RT timing. No source reported T-cell subsets, exhaustion markers, or clonality.
• Whether shrinking bulky, high-risk tumors with RT actually lowers the incidence or severity of CRS and ICANS.
• Whether RT safely allows bispecifics to continue during suspected tumor flare, or instead triggers CRS-like reactions.
• Whether comprehensive RT to residual PET-avid disease after a partial response improves outcomes compared with focal or no RT, and how to tell viable lymphoma from inflammation.
• Whether bispecific antitumor activity is truly delayed during step-up dosing.
• The antagonistic biological effects listed above.

Open questions include sequencing, dose, fractionation, target volume, and what “lymphocyte-sparing” RT should mean. Three prospective trials are registered (NCT07528352, NCT06867536, and NCT07634289), but none have reported results. The authors call for prospective, comparative trials with immune monitoring and radiation dosing analysis.

“RT is a treatment modality already central to lymphoma management and is now shown to be feasible alongside [bispecific] therapy in early experience,” the authors write. “It merits a genuine, trial-based answer on whether it can be integrated safely and with a benefit.”

References

1. Epkinly FDA approval history. Drugs.com. Updated July 8, 2024. Accessed September 23, 2026. https://www.drugs.com/history/epkinly.html
2. Columvi. Accessed September 23, 2026. https://www.drugs.com/columvi.html
3. Lunsumio FDA approval history. Drugs.com Updated January 5, 2026. Accessed September 23, 2026. https://www.drugs.com/history/lunsumio.html
4. Serani S. For a second time, FDA denies approval of odronextamab in lymphoma. Targeted Oncology. August 6, 2025. Accessed September 23, 2026. https://www.targetedonc.com/view/for-a-second-time-fda-denies-approval-of-odronextamab-in-lymphoma
5. Ciammella P, Bavieri A, Nizzoli ME, Alì E. Radiotherapy in combination with CD20×CD3 bispecific antibodies for B-cell lymphoma: biological rationale, current evidence, and open questions. Cancers. 2026;18(17):2895. doi:10.3390/cancers18172895
6. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913.
7. Linton K, Vitolo U, Jurczak W, et al. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol 2024;11: e593-e605
8. Baron JA, Chelius M, Singh G, et al. Safe integration of radiation therapy with bispecific antibodies in relapsed/refractory B-cell lymphomas. Clin Lymphoma Myeloma Leuk. Published online July 13, 2026 Jul 13:S2152-2650(26)00209-0. doi: 10.1016/j.clml.2026.07.004.