CAR-T ceLL for Eradication of Active Residual Disease in LBCL (CLEAR-1 Study)

Inclusion Criteria:

Eligibility for Pre-Screening:

1. Diagnosis: Histologically confirmed aggressive B cell NHL including the following types defined by WHO 2022\[1\]:

   • Diffuse large B cell lymphoma (DLBCL); OR

   • Primary mediastinal (thymic) large B cell lymphoma; OR

   • Transformation of indolent lymphomas (eg follicular lymphoma or marginal zone lymphoma)to DLBCL; OR
   * High grade B-cell Lymphoma (NOS, or with MYC/BCL2 rearrangements);
   * Double hit lymphoma (DHL) / Triple hit lymphoma (THL); OR
   * Follicular lymphoma grade 3b
2. Must have 10 unstained slides or tissue block from lymph node excision or core needle biopsy, or a lymph node biopsy (NOT FNA, bone or bone marrow biopsy), in 5 µm thickness FFPE with H\&E slide available for ctDNA calibration.
3. Must have intention to complete frontline chemoimmunotherapy including a CD20 monoclonal antibody and anthracycline.
4. In the investigator's assessment, is likely to be eligible to proceed to the treatment portion of this study with intention to undergo YTB323 if MRD positive.
5. Must be able to understand and the willingness to sign the written IRB approved pre-screening informed consent document.

Eligibility Criteria for Screening

1\. Diagnosis: Histologically confirmed aggressive B cell NHL including the following types defined by WHO 2022\[1\]:

* Diffuse large B cell lymphoma (DLBCL); OR
* Primary mediastinal (thymic) large B cell lymphoma; OR
* Transformation of indolent lymphomas to DLBCL; OR
* High grade B-cell Lymphoma;
* Double hit lymphoma (DHL) / Triple hit lymphoma (THL); OR
* Follicular lymphoma grade 3b

  2\. Must have completed planned frontline chemoimmunotherapy including a CD20 monoclonal antibody and anthracycline based therapy for LBCL indication with a CR or PR inaccessible for biopsy at end of treatment (EOT 1L).

  3\. Circulating tumor DNA is detectable by PhasED-seq within 12 weeks after completion of standard chemoimmunotherapy.

  6\. Normal Organ and Marrow Function

  \- ANC ≥ 1,000/uL
  * Platelet count ≥ 75,000/uL
  * Adequate renal, hepatic, pulmonary and cardiac function defined as:

    * Creatinine clearance (as estimated by Cockcroft Gault Equation) ≥ 45 mL/min
    * Serum ALT or AST ≤ 5 x ULN (except in subjects with liver involvement by lymphoma)
    * Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
    * Cardiac ejection fraction ≥ 40%, no evidence of pericardial effusion as determined by an Echocardiogram.
  * No clinically significant pleural effusion or ascites
  * Baseline oxygen saturation \> 92% on room air 7. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential) 8. Contraception: Subjects of child bearing or child fathering potential must be willing to practice birth control from the time of enrollment on this study and for twelve (12) months after receiving the preparative lymphodepletion regimen.

    9\. Must be able to understand and the willingness to sign the written IRB approved informed consent document. Subjects unable to give informed consent will not be eligible for this study.

    4\. Age 18 years or older 5. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2.

Exclusion Criteria:

\- 1. Prior treatment with CAR-T or adoptive cell therapy 2. Prior allogeneic transplant. 3. No bridging therapy permitted. 4. Active central nervous system disease from lymphoma. MRI of the brain with no evidence of CNS lymphoma if prior history of CNS involvement.

5\. Prior history of allergic reactions to any of the reagents used in the rapcabtagene autoleucel infusion.

6\. History of Richter's transformation of chronic leukemic lymphoma, small lymphocytic lymphoma, or lymphoplasmacytic lymphoma.

7\. History of T-cell histiocyte-rich large B-cell lymphoma. 8. Any medical condition that in the judgement of the investigator is likely to interfere with assessment of safety or efficacy of study treatment.

9\. Women who are pregnant or breastfeeding 10. History of invasive malignancy unless the patient has been disease-free for two years.

Exceptions include nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, and breast) and low grade prostate cancer (e.g. Gleason 3+3) Hormonal therapy in subjects in remission \>1 year will be allowed. 11. History of stroke or transient ischemic attack within 12 months before enrollment, or seizure disorders requiring active anticonvulsive medication.

12\. In the investigator's judgment, the subject is unlikely to complete all study-specific visits or procedures, including follow-up visits, or comply with the study requirements for participation.