Bispecific Antibodies Post-CAR-T for Lymphoma

Recruiting at 1 trial location

Overseen By Kaitlin Kennard, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Abramson Cancer Center of the University of Pennsylvania

Must not be taking: Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune disease, Cardiovascular disease, Infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 9 weeks

42 Participants Needed

Trial Summary

What is the purpose of this trial?

The research study is being conducted to test the safety and effectiveness of the experimental drug mosunetuzumab (Cohort 1) or obinutuzumab and glofitamab (Cohort 2) when given after CAR (genetically modified) T cells. The study is for patients who have already received a CAR T-cell infusion. Some patients who join the study will receive mosunetuzumab, other patients later in the study may receive a different experimental drug (glofitamab, in combination with obinutuzumab).

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic immunosuppressive medications, you may need to stop them before starting the study treatment.

What data supports the effectiveness of the treatment Bispecific Antibodies Post-CAR-T for Lymphoma?

Bispecific antibodies have shown promise in treating relapsed or refractory B-cell lymphomas by directing T cells to attack cancer cells, even when CAR T-cell therapy fails. Early clinical trials have demonstrated their potential effectiveness, particularly in cases where traditional CAR T-cell therapies have not succeeded. ^{1 2 3 4 5}

Is CAR-T cell therapy generally safe for humans?

CAR-T cell therapy, while effective for certain cancers, can have serious safety concerns, including life-threatening toxicities and increased risk of infections. These side effects can affect multiple organs and require careful management by healthcare professionals. ^{6 7 8 9 10}

How is the treatment with bispecific antibodies post-CAR-T for lymphoma different from other treatments?

This treatment is unique because it uses bispecific antibodies, which are engineered to connect T-cells (a type of immune cell) directly to cancer cells, helping the immune system target and destroy the cancer more effectively. Unlike traditional treatments, bispecific antibodies do not rely on the body's usual antigen presentation process, making them a novel approach for patients who have not responded to CAR-T therapy. ^{5 11 12 13 14}

Research Team

Stephen Schuster, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for patients with relapsed or refractory large B-cell lymphoma who have tried at least two treatments, including one with an anthracycline and another targeting CD20. They must be post CAR T-cell therapy by at least 30 days, have a life expectancy of over 12 weeks, measurable disease on scans, and adequate lab results. Participants need to commit to contraception and not be pregnant.

Inclusion Criteria

It has been over 30 days since my CAR T-cell treatment.

It has been over 30 days since my CAR T-cell treatment.

I've had a recent scan showing a measurable cancer lesion before CAR-T cell therapy.

Exclusion Criteria

I need oxygen or steroids for my lung condition.

I do not have any current infections or have been hospitalized for one in the last 2 weeks.

History of drug or alcohol abuse within 12 months prior to screening in the investigator's judgment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mosunetuzumab or obinutuzumab and glofitamab following CAR T-cell therapy

9 weeks

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Long-term follow-up

Participants are monitored for response duration and long-term safety

Up to 5 years

Treatment Details

Interventions

• CAR-T
• Glofitamab
• Mosunetuzumab
• Obinutuzumab

Trial Overview The study tests the safety and effectiveness of mosunetuzumab alone (Cohort 1) or combined obinutuzumab and glofitamab (Cohort 2) following CAR T-cell treatment. Patients are assigned to receive either mosunetuzumab first or the combination drugs later in the study.

Participant Groups

Group I: Cohort 2 Experimental Treatment 2 Interventions

Participants receive obinutuzumab (1000 mg for each subject) and glofitamab after standard-of-care therapy with CD19-directed CAR T-cells. The dose of glofitamab for each subject will be 30 mg, other than for cycle 1, which will be 12.5 mg glofitamab fractionated over two weeks.

Group II: Cohort 1 Experimental Treatment 1 Intervention

Participants receive mosunetuzumab 60 mg for cycles 1 and 2 (although fractionated for cycle 1), and 30 mg for all subsequent cycles after standard-of-care therapy with CD19-directed CAR T-cells

CAR-T is already approved in United States, European Union, Canada for the following indications:

Approved in United States as CAR T-cell therapy for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
• High-grade B-cell lymphoma
• Primary mediastinal B-cell lymphoma
• Follicular lymphoma

Approved in European Union as CAR T-cell therapy for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
• High-grade B-cell lymphoma
• Primary mediastinal B-cell lymphoma
• Follicular lymphoma

Approved in Canada as CAR T-cell therapy for:

• Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
• High-grade B-cell lymphoma
• Primary mediastinal B-cell lymphoma
• Follicular lymphoma

Who Is Running the Clinical Trial?

Abramson Cancer Center of the University of Pennsylvania

Lead Sponsor

Trials

360

Recruited

108,000+

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

CD79b is widely expressed on tumor cells in various types of B-cell lymphomas, making it a promising target for CAR T-cell therapy.

Anti-CD79b CAR T-cells demonstrated high specificity and effectiveness in treating B-cell lymphomas, suggesting that targeting CD79b could improve outcomes for patients who do not respond to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD79b for Chimeric Antigen Receptor T-Cell Therapy of B-Cell Lymphomas. Ding, S., Mao, X., Cao, Y., et al.[2021]

In a study of 32 patients with relapsed or refractory B cell non-Hodgkin lymphoma, bispecific CD19/22 CAR T cell therapy showed a high overall response rate of 79.3% and a complete response rate of 34.5%, indicating its potential efficacy as a treatment option.

While the therapy demonstrated promising results, it was associated with significant safety concerns, including severe cytokine release syndrome in 28.1% of patients and grade 3 or higher neurologic events in 12.5%, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma. Zhang, Y., Li, J., Lou, X., et al.[2022]

A study of 521 lymphoma patients showed that using PET/CT scans before autologous stem-cell transplantation (ASCT) significantly improved the identification of patients who would benefit from the procedure, leading to better overall survival rates over time (from 66% to 83% over three periods).

Patients who achieved a complete response (PET/CT-CR) had excellent outcomes, with 2-year overall survival rates of 87% for relapsed/refractory aggressive B-cell lymphoma and 91% for peripheral T-cell lymphoma, suggesting that ASCT remains a vital part of lymphoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The value of complete remission according to positron emission tomography prior to autologous stem cell transplantation in lymphoma: a population-based study showing improved outcome. Noring, K., Carlsten, M., Sonnevi, K., et al.[2021]

CAR T-cell therapy targeting CD19 has significantly improved treatment outcomes for relapsed/refractory B-cell malignancies, but many patients still experience relapses due to antigen loss.

Bispecific CAR T-cells, such as those targeting CD19/CD20 and CD19/CD22, show promising efficacy and safety in early phase I trials, suggesting they may help reduce relapse rates, though further research in larger phase II studies is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific CAR T-cells for B-cell Malignancies. Furqan, F., Shah, NN.[2022]

Bispecific antibodies can effectively direct T cell-mediated cytotoxicity towards cancer cells by linking T cells to tumor antigens, allowing for targeted treatment without needing traditional antigen presentation methods.

Early phase 1 clinical trials of bispecific antibodies targeting CD20 and engaging T cells via CD3 show promise for treating relapsed or refractory B-cell lymphomas, highlighting their potential as a therapeutic option, especially in cases where CAR T cell therapies have failed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific antibodies for the treatment of lymphomas: Promises and challenges. Schuster, SJ.[2021]

In a study of 50 patients receiving CD19 CAR-T cell therapy, 36% experienced infectious complications, with a median time to infection of 225 days, indicating that infections can occur well after treatment.

Severe infections were common, with 54.8% leading to significant health issues, including hospitalization and even death in 6% of patients, highlighting the need for ongoing monitoring and improved antimicrobial prophylaxis strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience. Walker, B., Zimmer, AJ., Stohs, EJ., et al.[2023]

CAR-T cell therapy has shown remarkable efficacy in treating B cell malignancies, including leukemia, lymphoma, and multiple myeloma, with high response rates, but it comes with significant safety concerns.

The most serious side effects of CAR-T therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which require supportive care and specific treatments like tocilizumab and steroids to manage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy: the Efficacy and Toxicity Balance. Chohan, KL., Siegler, EL., Kenderian, SS.[2023]

CAR T cell therapy has shown great promise in treating certain blood cancers, but it can lead to serious side effects, including potentially fatal toxicities from cytokine release and off-target effects that harm healthy tissues.

Recent strategies to improve safety include modifying CAR structures and incorporating elements like switch molecules and suicide genes to reduce the toxic effects of CAR T cells on normal tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for modifying the chimeric antigen receptor (CAR) to improve safety and reduce toxicity in CAR T cell therapy for cancer. Sayadmanesh, A., Yekehfallah, V., Valizadeh, A., et al.[2023]

CAR T cell therapy is effective in treating B cell malignancies like acute lymphoblastic leukemia and non-Hodgkin lymphomas, but it can also cause serious side effects, including multi-organ failure.

Early recognition and management of side effects such as cytokine release syndrome and neurotoxicity are crucial for healthcare staff to ensure patient safety during CAR T cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I treat adverse effects of CAR-T cell therapy. Yáñez, L., Alarcón, A., Sánchez-Escamilla, M., et al.[2021]

CAR-T cell therapy shows promising efficacy in treating relapsed/refractory B-cell lymphoma, particularly in older patients and those with specific pathological types, achieving high response and complete remission rates across 17 studies.

While the treatment is generally safe, with most side effects like cytokine-releasing syndrome (CRS) and neurotoxicity being reversible, careful monitoring of these toxicities is essential during clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma: a systematic review and meta-analysis. Zheng, XH., Zhang, XY., Dong, QQ., et al.[2023]

Bispecific antibodies are a promising new immunotherapy for treating cancers like non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), showing encouraging results in early-phase studies for patients with poor-risk B cell NHL and MM.

Several bispecific antibody constructs are currently in clinical development, indicating a growing interest and potential for these therapies in improving cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific antibodies for non-Hodgkin's lymphomas and multiple myeloma. Castaneda-Puglianini, O., Chavez, JC.[2021]

Bispecific antibodies are a promising immunotherapy for cancer, as they can effectively link immune cells to tumor cells, enhancing the immune response through dual specificity for both tumor-associated antigens and lymphocyte activation sites.

This approach leverages the body's natural immune defense system, resulting in only minor toxicity compared to traditional therapies, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell targeting in cancer therapy. Bolhuis, RL., Sturm, E., Braakman, E.[2020]

T-cell bispecific antibodies (TCBs) are engineered to activate T-cells against tumors by binding to both T-cell receptors and tumor-associated antigens, enhancing tumor cell killing.

The novel TCRL-CAR-J approach allows for efficient identification of selective TCR-like antibodies (TCRLs) by using CARs in reporter cells, streamlining the process of developing TCRL-TCBs without needing to produce each candidate in the final format.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-J cells for antibody discovery and lead optimization of TCR-like immunoglobulins. Jost, C., Darowski, D., Challier, J., et al.[2021]

Bispecific antibodies have demonstrated the ability to selectively target and effectively eliminate malignant T cells in both laboratory (in vitro) and living organism (in vivo) settings.

This selectivity and efficacy suggest that bispecific antibodies could be a promising therapeutic approach for treating cancers involving T cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell Malignancies Can Be Targeted by Bispecific Antibody Treatments. [2021]

References

1. France pubmed.ncbi.nlm.nih.gov

Targeting CD79b for Chimeric Antigen Receptor T-Cell Therapy of B-Cell Lymphomas. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

A Prospective Investigation of Bispecific CD19/22 CAR T Cell Therapy in Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

The value of complete remission according to positron emission tomography prior to autologous stem cell transplantation in lymphoma: a population-based study showing improved outcome. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Bispecific CAR T-cells for B-cell Malignancies. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Bispecific antibodies for the treatment of lymphomas: Promises and challenges. [2021]

6. Denmark pubmed.ncbi.nlm.nih.gov

Infectious complications among CD19 CAR-T cell therapy recipients: A single-center experience. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy: the Efficacy and Toxicity Balance. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Strategies for modifying the chimeric antigen receptor (CAR) to improve safety and reduce toxicity in CAR T cell therapy for cancer. [2023]

9. England pubmed.ncbi.nlm.nih.gov

How I treat adverse effects of CAR-T cell therapy. [2021]

10. China pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma: a systematic review and meta-analysis. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Bispecific antibodies for non-Hodgkin's lymphomas and multiple myeloma. [2021]

12. Germany pubmed.ncbi.nlm.nih.gov

T cell targeting in cancer therapy. [2020]

13. United States pubmed.ncbi.nlm.nih.gov

CAR-J cells for antibody discovery and lead optimization of TCR-like immunoglobulins. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

T-cell Malignancies Can Be Targeted by Bispecific Antibody Treatments. [2021]