CAR-T Cell Therapy, Mosunetuzumab and Polatuzumab for Treatment of Refractory/Relapsed Aggressive Non-Hodgkin's Lymphoma (NHL).

Inclusion Criteria:

1. Histologic diagnosis of:

2. Diffuse large B cell lymphoma (DLBCL) not otherwise specified. Patients withprimary cutaneous DLBCL of leg-type are eligible if the lymphoma expressescluster of differentiation 19 (CD19) and if the insurance approves the CAR-Ttherapy. Similarly. Large cell transformation of nodal or extra-nodal marginalzone lymphoma is eligible only if the insurance allows and the disease showsstrong CD19 positivity. On the other hand, post-transplant lymphoproliferativedisorders (PTLD) are not allowed due to the frequently required continuation ofimmunosuppression to avoid organ rejection.

3. Primary mediastinal B cell lymphoma (PMBCL)

4. Transformed follicular lymphoma (TFL). An untransformed follicular lymphomagrade 3B will be considered on a case by case basis, since the geneticsignature of grade 3B follicular lymphoma frequently resemble that of DLBCL andthe large lymphomatous cells just happen to be organized in a follicularpattern. Recently, Breyanzi has an FDA indication for follicular lymphoma grade 3B.

5. High grade B cell lymphoma (HGBL), other than B-lymphoblastic lymphoma

6. Mantle Cell lymphoma (MCL)

7. Burkitt lymphoma (BL): Although very few reports inform us about the outcome ofrelapsed/refractory BL, encouraging activity including CRs have been reportedwith CAR-T and these patients are in need because they do not have enoughoptions available. We will need insurance approval for such enrollment.

8. Additionally, the lymphoma has to be in one of the following status:

9. Primary refractory which for the purpose of this study is defined as failure toobtain any response (PR or CR) after at least 3 cycles of anthracycline-basedtherapy or persistent disease after 6 cycles of anthracycline-based therapy asdocumented by a PET/CT scan that is done no later than 2 months after the last (usually the 6th) cycle of primary chemotherapy. In questionable cases, abiopsy should confirm persistence of disease as part of standard of care. Incase of mantle cell lymphoma, the primary therapy if does not include ananthracycline, should include either high doses of cytarabine +/-bendamustineand an anti-CD20 antibody (usually rituximab).

10. Relapsed disease that fails to respond (CR or PR) after at least 2 cycles of aplatinum and/or cytarabine-based chemotherapy. For the purpose of this study,appropriate regimens include: rituximab, ifosfamide, carboplatin and etoposide (R-ICE), rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP),rituximab dexamethasone cytarabine oxaliplatin (R-DHAOx), rituximab,gemcitabine, cisplatin, and dexamethasone (R-GDP). Rituximab, gemcitabine, andoxaliplatin (R-Gem-Ox) is considered appropriate if the patient fails to obtainat least a PR after 4 doses of oxaliplatin. Patients with MCL who relapse afteran anthracycline, bendamustine or cytarabine-based regimen, should have failedtwo salvage attempts: a molecularly targeting-based regimen including at leasta Bruton's tyrosine kinase (BTK) inhibitor with or without venetoclax and acytotoxic traditional second salvage regimen, unless the two salvage approachesare combined. For example if they fail a salvage with R-ICE + a BTK-inhibitorin combination, they are eligible without the need to be exposed to moretherapy. Patients with PMBCL, they should also have failed a traditionalsalvage regimen and a programmed cell death protein 1 (PD-1) inhibitor-basedsalvage.

11. Relapse after an autologous stem cell transplantation. At least 3 months shouldhave lapsed between autologous stem cell infusion and initiation of pre-CAR-Tlymphodepleting chemotherapy due to the risk of prolonged cytopenias.

12. At least one of the lymphoma lesions should be measurable. For the purpose of thisstudy an involved nodal lesion should be at least 1.5 cm in the longest diameter,while extra-nodal lymphoma lesions should have their longest diameter ≥1.0 cm

13. Lymphoma cells need to be CD19 positive. In case of previous therapy with ananti-CD19 agent (including but not limited to blinatumomab, tafasitamab,loncastuximab tesirine), a new biopsy should be performed to confirm CD19positivity.

14. The performance status of the patient as measured by the Eastern CooperativeOncology Group (ECOG) performance scale should be 0 - 2 (ECOG performance status (PS):0-2).

15. Only adult patients will be eligible (patient age >18 years old). Patients up to 80years old will be considered to participate in the study assuming they fulfill allthe other inclusion criteria

16. The creatinine clearance as measured by the Cockcroft-Gault equation should be 50mL/min or better (CrCl ≥ 50 mL/min).

17. Unless the patient has a known Gilbert syndrome, the total Bilirubin should be lessthat 1.5 x upper limit of normal (ULN) and both the transaminases (ALT and AST)should be less than 2.5 x ULN. The only exception to this rule is lymphomainfiltration of the liver where values of total Bilirubin up to 3 x ULN andtransaminases up to 5 x ULN will be allowed after communication with the PrincipalInvestigator (P.I. or his/her designee)

18. The ejection fraction of the left ventricle as it is estimated on the Echocardiogram (preferably) or on the multigated acquisition (MUGA) scan should be at least 45% (LVEF ≥ 45%).

19. The oxygen saturation of oxyhemoglobin on room air as measured by pulse oximetryshould be at least 94% (O2Sat ≥ 94%). If a technical problem (artifact) is suspectedon pulse oximetry, arterial blood gases will be obtained for more accuratemeasurement.

20. On the day of screening and assuming there will be no other than the protocoltherapy, the patient should have at least the following:

21. Absolute neutrophil count >1000/microliter,

22. Hg> 8 grams/ deciliter

23. Absolute lymphocyte count >250/microliter

24. Platelet count >75,000/microliter

25. Patient should not have a transfusion of packed red blood cells (PRBCs) or plateletsor receive erythropoietin analogues thrombopoietin receptor agonist (Tpo-mimetic),granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophagecolony-stimulating factor (GM-CSF) for at least 5 days before the officialdetermination of eligibility takes place.

26. Patient should sign an informed consent and be willing to comply with theanticipated labs and clinic visits and should be willing to be hospitalized andundergo the required invasive procedures as directed by the treating Investigator.

27. Female subjects should have a negative serum pregnancy test, unless they confirmtheir menopausal status and/or have undergone previous hysterectomy and/oroophorectomy.

28. Both men and women with childbearing potential should agree to use effectivecontraception for the duration of the treatment and for at least 1 year after thelast treatment since medications (e.g. cyclophosphamide) that will be used in theprotocol can be harmful for the embryo.

Exclusion Criteria:

1. Patients with EBV+DLBCL, plasmablastic lymphoma, human herpesvirus-8 (HHV-8) relatedB cell lymphoproliferative disorders including primary effusion lymphoma, anaplasticlymphoma kinase (ALK)+ LBCL, intravascular large B cell lymphomas, DLBCL associatedwith chronic inflammation, lymphomatoid granulomatosis, primary DLBCL of the CNS andT cell histiocyte rich LBCL will not be allowed because of different biology,frequent lack of CD19, difficulty in interpreting toxicity (as in the case ofprimary central nervous system (CNS) lymphoma) or some preliminary discouragingresults with CAR-T as in the case of T-cell, histiocyte-rich large B cell lymphomaand Richter transformation of chronic lymphocytic leukemia (CLL).

2. Primary CNS lymphoma or secondary CNS involvement by lymphoma.

3. Similarly, patients with conditions that increase the risk of CNS toxicity will beexcluded. Such conditions include but not limited to

4. active seizure disorder for which an antiepileptic is taken,

5. demyelinating diseases like multiple sclerosis

6. history of ischemic or hemorrhagic stroke in the last 2 years

7. Neurodegenerative disorders like Alzheimer and Parkinson

8. Cerebral edema or hydrocephalus of any cause

9. Invasive sarcoma or carcinoma in the last 3 years, except from localized basal orsquamous cell carcinomas of the skin, or cervical carcinoma in situ. LocalizedGleason <7, prostate-specific antigen (PSA)<10 prostatic adenocarcinoma T1-2N0M0under active surveillance is allowed.

10. Myocardial infarction or unstable angina or coronary revascularization within 6months of protocol enrollment is not allowed. Stable angina that requires nitratesfor pain relief is not allowed either because of concerns of hypotension during theCRS period.

11. Systemic hypertension that is not controlled with maximum three antihypertensives toa level of <160/100 precludes enrollment.

12. Uncontrolled invasive infection, including fungal pneumonia, fungal sinusitis orfungal encephalitis are not allowed and should be resolved completely beforeenrollment. Cytomegalovirus (CMV) viremia>200 copies/microliter or EBV viremia > 1000 copies/microliter are not allowed unless treated completely in the case of CMVviremia and the patient then is placed on prophylactic letermovir.

13. Patients with history of macrophage activation syndrome (MAS)/hemophagocyticlymphohistiocytosis (HLH) and patients with known or suspected chronic activeEpstein Barr Virus infection (CAEBV).

14. HIV positivity is allowed as long as the viral load of HIV-1 is less than 200copies/microliter the last 3 months and the patient continue at least 3antiretroviral agents during therapy.

15. Chronic hepatitis B should have been controlled to hepatitis B virus (HBV) viralload <200 copies/microliter and patients with chronic hepatitis B or even with justhistory of exposure to hepatitis B (hepatitis B core antibody positive but surfaceantigen negative) should be on suppressive therapy with entecavir, lamivudine orequivalent.

16. Patients with hepatitis C and clearance of the virus with previous therapy areallowed as long as they do not suffer from chronic liver dysfunction. Patients withchronic hepatitis C and normal hepatic function should be cleared by a Hepatologistbefore inclusion and at least an elastogram and an ultrasound should be performed tor/o well-compensated cirrhosis.

17. Autoimmune disorders including rheumatoid arthritis, severe psoriasis, systemiclupus erythematosus, scleroderma with pulmonary involvement, polymyositis, systemicvasculitis and inflammatory bowel disease requiring treatment with more than oralbudesonide or nonacetylated salicylates are not allowed. Similarly pneumonitis,including cryptogenic organizing pneumonia, bronchiolitis obliterans or eosinophilicpneumonias or sarcoidosis affecting the lung parenchyma are not allowed. GuillainBarre, autoimmune hepatitis and autoimmune encephalitis as well asglomerulonephritis with nephrotic or nephritic syndrome are not allowed. Addison isallowed but prednisone daily dose should be less than 10 mg/d. Hashimoto thyroiditisis allowed as long as the patient has well controlled thyroid function withsupplemental levothyroxine. Grave's disease has to be in excellent control withprevious surgery or radioiodine or with methimazole with or without beta blockersbut not glucocorticosteroids and patients will need endocrinology consultationbefore the enrollment.

18. Other causes of congenital or acquired immunodeficiencies other than common variableimmunodeficiency or immunoglobulin A (IgA) deficiency are not allowed.

19. External drains including pericardial, pleural, peritoneal, external biliary drainsor nephrostomies are not allowed.

20. Use of prednisone for any reason should not be >10 mg/d. All other systemicimmunosuppressive agents are not allowed.

21. Any biologic agent interfering with the immune system function or cytotoxicchemotherapy are not allowed within 21 days of the first dose of mosunetuzumab.Radiation is not allowed within 14 days of the first mosunetuzumab administration.If temporary control of the lymphoma is required, only dexamethasone 20 mg/d for upto 5 days before the first administration of mosunetuzumab is allowed.

22. Patient should not have anti-human leukocyte antigen (HLA) antibodies that make themrefractory to platelets transfusions.

23. If patients are on systemic antiplatelet or anticoagulant therapy, this therapy hasto be stopped. Patients can continue low dose acetylsalicylic acid (ASA) up to 100mg/d that will be also stopped when platelets drop below 75,000/microliter at anypoint during therapy. Non catheter-related deep venous thrombosis or pulmonaryembolism that happened less than 3 months before protocol enrollment are notallowed.

24. Any cardiac disease in addition to left ventricular ejection fraction (LVEF) <45%that gives symptoms of heart failure (diastolic dysfunction or valvularabnormalities or dysrhythmias) and makes the patient belong to New York HeartAssociation (NYHA) II-IV functional group, automatically makes the patientineligible.

25. Previous anti-CD19 CAR-T therapy is not allowed.

26. Uncontrolled Psychosis or cognitive impairment that makes the patient unable to makeinformed decisions preclude participation.

27. Previous solid organ transplantation precludes participation.