Glofitamab in B-NHL Using Mid-Therapy Intratumoral Transcriptomics

Inclusion Criteria: * Patients with pathologically confirmed diagnosis of aggressive CD20(+) B-NHL, * including DLBCL and MCL. * Stage II, III or IV by Ann Arbor Classification. * Superficially accessible lesion for core-needle biopsy, e.g. cervical, axillary, * inguinal, subcutaneous. * Disease that has progressed (clinically or radiographically) after standard-of-care * prior therapy, including anthracycline-based therapy for DLBCL and anti-CD20 * mAb-based therapy for all histologies. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from study entry: * Contraindication to any of the individual components of glofitamab or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products * Any prior treatment with a BsAb targeting CD3 and CD20 * Prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation * Prior treatment with systemic immunotherapeutic agents, including but not limited to, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (mAbs) (e.g., anti-cytotoxic T lymphocyte associated protein 4, anti-PD-1, and anti-PD-L1) within 4 weeks or five half-lives of the drug, whichever is shorter * Treatment with CAR-T therapy within 30 days prior to first dose of glofitamab * Any investigational therapy for the purposes of treating cancer within 28 days prior to the start of Cycle 1 * Prior radiotherapy to the mediastinal/pericardial region Radiotherapy to non-target lesion sites will be permitted. * Corticosteroid use \>50 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control * Participants receiving corticosteroid treatment with \>50 mg/day of prednisone or equivalent for reasons other than lymphoma symptom control (e.g., rheumatoid arthritis) must be documented to be on a stable dose of at least 4 weeks duration prior to the start of Cycle 1. * Corticosteroid therapy for control of cancer symptoms or side effects of prior treatment (e.g., nausea or B-symptoms) is permitted. * The use of inhaled corticosteroids is permitted. * The use of mineralocorticoids for management of orthostatic hypotension is permitted. * The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted. * Participants who require lymphoma symptom control during screening may receive steroids in the following manner: * Up to 50 mg/day of prednisone or equivalent may be used for lymphoma symptom control during screening, including prior to finalization of staging (not included as part of pre-phase treatment). * If glucocorticoid treatment is urgently required at higher doses for lymphoma symptom control prior to the start of study treatment, tumor assessments must be completed prior to initiation of 50-100 mg/day of prednisone or equivalent. Prednisone 50-100 mg/day or equivalent may be given for a maximum of 10-14 days as a pre-phase treatment. As part of the pre-phase treatment, vincristine may not be administered. * History of other malignancy that could affect compliance with the protocol or interpretation of results: * Participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix at any time prior to the study are eligible. * Participants with any malignancy appropriately treated with curative intent and the malignancy has been in remission without treatment for \> 2 years prior to enrollment are eligible. * Participants with low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible. * Significant or extensive history of cardiovascular disease such as New York Heart Association Class III or IV cardiac disease or Objective Assessment Class C or D, myocardial infarction within the last 3 months prior to the start of Cycle 1, unstable arrhythmias, or unstable angina * Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis * Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis or neurodegenerative disease Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurological deficits, as judged by the investigator, are allowed. * Current or past history of CNS lymphoma * Known or suspected history of hemophagocytic lymphohistiocytosis (HLH) * Current or past history of Waldenström macroglobulinemia * History or presence of an abnormal ECG that is clinically significant in the investigator's opinion * Patients with known or suspected active infection, or reactivation of a latent infection, whether bacterial, viral (including, but not limited to, SARS-Cov-2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B, and hepatitis C), fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks of dosing * History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents, as follows: * Grade 3 or higher adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy. * Grade 1-2 adverse events that did not resolve to baseline after treatment discontinuation. * Clinically significant liver disease, including active viral or other hepatitis or cirrhosis * Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment * Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma): * INR or PT \> 1.5 x upper limit of normal (ULN) in the absence of therapeutic anticoagulation. * PTT or aPTT \>1.5 x ULN in the absence of a lupus anticoagulant. * Serum AST and ALT \>2.5 x ULN. * Total bilirubin \>1.5 x ULN. Participants with documented Gilbert disease may be enrolled if total bilirubin is \> 3.0 x ULN. * Live, attenuated vaccine within 4 weeks before study treatment infusion on Day 1 of Cycle 1 or anticipation that such a live, attenuated vaccine will be required during the study. Live vaccines during the study and until participants B cells recover, are prohibited Influenza vaccination should be given during influenza season only. Participants must not receive live, attenuated influenza vaccine at any time during the study treatment period. * Suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay) * Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HBsAg\] serology) Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. Such participants must be willing to undergo HBV DNA testing on Day 1 of every cycle and every 3 months for at least 12 months after the final cycle of study treatment and appropriate antiviral therapy as indicated. * Positive test results for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing) Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. * Positive test results for HTLV-1 * Participants with a history of progressive multifocal leukoencephalopathy * Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 18 months after pretreatment with obinutuzumab or 2 months after the final dose of glofitamab, whichever is longer * Positive SARS-CoV-2 test within 7 days prior to enrollment. Rapid antigen test result is also acceptable.