This study is being done to determine if we can lower the chance of diffuse large B-cell lymphoma (DLBCL) growing or spreading by adding treatment to the usual therapy.

The purpose of this study is to compare the usual treatment alone to using the study drugs mosunetuzumab and/or polatuzumab vedotin after CAR T-cell therapy. The usual approach for relapsed/refractory DLBCL patients is follow-up visits with no further therapy. We are doing this study because we want to find out if this approach is better or worse than the usual approach for DLBCL patients receiving CAR T-cell therapy.

Mosunetuzumab is an experimental drug known as a bispecific antibody targeting CD20 and CD3. This antibody brings the T-cells of the immune system and the lymphoma cells together so that the immune system can potentially destroy the lymphoma cells. Experimental means that mosunetuzumab is not approved by the U.S. Food and Drug Administration (FDA).

Polatuzumab vedotin is an antibody–drug conjugate which targets CD79b, a molecule that is on the surface of B-cell lymphoma cells. Antibody-drug conjugates consist of an antibody against the tumor cell that is attached to a chemotherapy drug. The antibody brings the chemotherapy drug to the lymphoma cell so that it can potentially destroy the lymphoma cell. Polatuzumab vedotin is approved by the FDA in combination with bendamustine and a rituximab product for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, after at least two prior therapies.

After receiving CAR T-cell therapy, participants in this study will be randomized into one of four treatment groups. There is an equal chance of being assigned to any of the groups. The study team will discuss dosing and treatment specifics with each participant depending on the group they are assigned. Treatment cycles typically last 21 days.

• Group 1 will receive mosunetuzumab through a vein in the arm for 8 cycles of treatment.
• Group 2 will receive polatuzumab vedotin through a vein in the arm for 6 cycles of treatment.
• Group 3 will receive both mosunetuzumab and polatuzumab vedotin through a vein in the arm for up to 8 cycles of treatment.
• Group 4 will not receive any study drugs and will be monitored closely by the study team. Participants in this group will have the option to “crossover” to Group 3 if their cancer gets worse within 12 months of CAR T-cell therapy.

After completing study treatment, all participants will come in for study visits every 3 to 6 months for up to 5 years. Study visits may include physical exams, blood tests, and scans.