Lymphodepletion With Low Dose Total Body Irradiation Before Standard of Care Tisagenlecleucel for the Treatment of Relapsed and Recurrent Large B-cell Lymphoma

Inclusion Criteria:

* Eligible for standard of care anti-CD19 CAR-T treatment with Tisa-cel
* Age ≥ 18 years
* Biopsy-confirmed relapsed or refractory large B-cell lymphoma after 2 lines of prior therapy
* Qualitative CD19 expression by either immunohistochemistry (IHC) or flow cytometry
* Measurable disease prior to lymphodepletion as determined by Lugano criteria
* Non-RT bridging therapy allowed, but requires re-staging prior to lymphodepletion (LD) to confirm measurable disease
* Adequate performance status Eastern Cooperative Oncology Group (ECOG) ≤ 2
* Platelets above 75K
* Hemoglobin above 8.0 g/dL without transfusion within 1 week
* Absolute neutrophil count (ANC) above 1,000 without granulocyte colony-stimulating factor (G-CSF) within 1 week
* Total bilirubin \< 1.5 x upper limit of normal (ULN)
* Alanine aminotransferase (ALT) =\< 3 x ULN
* Glomerular filtration rate (GFR) \> 60 ml/min calculated by the Cockcroft - Gault formula
* Oxygen saturation (SpO2) \> 92% without supplemental oxygen
* Ejection fraction more than 45%
* Patients must have the ability to understand and the willingness to sign a written informed consent document
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of \< 1% per year during the treatment period and for at least 12 months after Tisa-cel and until CAR T-cells are no longer present by quantitative polymerase chain reaction (qPCR) on two consecutive tests
* A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (\< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptive s that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
* The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
* For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

  * With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 12 months after Tisa-cel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. Men must refrain from donating sperm during this same period
  * With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 6 months after Tisa-cel infusion to avoid potential embryonal or fetal exposure. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
* For patients with prior irradiation: the study radiation oncologist co-investigator will review the patient's prior history of radiation to confirm that the investigational low dose total body irradiation is feasible and safe to respect the maximum cumulative organ radiation exposure

Exclusion Criteria:

* Active central nervous system (CNS) disease at screening or prior to lymphodepletion
* Prior therapy with autologous or allogenic CAR-T or CAR-natural killer (NK) cell therapy
* Prior anti-CD19 therapies (such as, but not limited to tafasitamab or loncastuximab)
* Prior allogeneic stem cell transplant
* Bridging therapy with radiation not allowed
* Any contra-indications to receive low-dose TBI, standard of care lymphodepleting chemotherapy or Tisa-cel per treating physician
* A minimum of 28 days must have elapsed between prior treatment with investigational agent(s) and start of lymphodepletion
* Uncontrolled major medical problem as infections
* Active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast). Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial (e.g. low Gleason score prostate cancer)
* Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study
* Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy
* Active hepatitis B or C as indicated by serology (for details please refer to Novartis Leukapheresis Reference Manual version \[v\] 4)
* Patients with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease
* History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of systemic immunosuppressive medication within 6 months
* Live vaccines given in 28 days prior to lymphodepleting chemotherapy
* Active substance use disorders