This study evaluates the feasibility and safety of bridging radiation therapy, including a novel method for comparing the effectiveness of hypofractionated versus hyperfractionated radiation therapy in participants with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) undergoing T-cell redirection therapies (CAR T-cell therapy or bispecific antibodies).

The purpose of this study is to assess the feasibility and safety of bridging radiation, including a novel method to study the relative effectiveness of hypo- vs. hyperfractionated therapy (i.e., once daily vs. twice daily treatment) in patients with R/R DLBCL undergoing T-cell redirection therapies. This trial will serve as proof-of-concept, feasibility, and safety for a novel dual fractionation trial design, treating the same tumor with two fractionation schedules, paving the way for future radiotherapy trial designs and direct comparison of the efficacy of once vs. twice daily treatment. Correlative studies of immune exhaustion will evaluate the mechanistic underpinnings between radiotherapy and the immune environment. Finally, with the use of RefleXion BGRT, we will collect PET imaging data to provide the basis for this emerging method for administering bridging radiation in lymphoma.

Inclusion Criteria:

1. Provision of signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Adult aged 18 years or older.
4. Histologically confirmed diagnosis of R/R DLBCL with plan for CAR T or BsAb therapy at Yale New Haven Hospital.
5. ECOG performance status 0 to 3.
6. Ability to present for once or twice daily (M-F) fractionated radiation therapy, without contraindications for radiotherapy as determined by the treating radiation oncologist.
7. Women of childbearing potential must have a negative serum or urine pregnancy test at screening and at time of radiation treatment planning, per standard of care and departmental standard operating procedure. Participants must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed.

Exclusion Criteria:

Participants who meet any of the following criteria will be disqualified from entering the study:

1. Participants who are pregnant or currently breastfeeding.

   a. Females who have undergone surgical sterilization or who have been postmenopausal for at least 12 months are not considered to be of childbearing potential.

2. Participants with history of prior radiation exposure for research purposes within the past year, such that participation in this study would place them over the FDA limits for annual radiation exposure.

3. Participants who are unable to safely receive FDG PET tracer.

4. Any condition that would, in the investigator's judgment, interfere with full participation in the study and attending required study visits (if outpatient); pose a significant risk to the participant; or interfere with interpretation of study data.

5. Participants who would not be anticipated to derive any clinical benefit from bridging radiotherapy, are unable to participate in twice daily radiotherapy, or have clinical contraindications to radiation therapy per treating investigator.