BAFF CAR-T Cells for Chronic Lymphocytic Leukemia

Overseen By Paolo Caimi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Paolo Caimi, MD

Must be taking: Obinutuzumab

Must not be taking: Immunosuppressants

Disqualifiers: Active infection, CNS involvement, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

18 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that you must wait more than 2 weeks since prior radiation therapy or 5 half-lives for systemic therapy before leukapheresis, and you cannot use corticosteroids within 2 days before the infusion, except for preventing nausea during chemotherapy.

What data supports the effectiveness of the treatment BAFF CAR-T Cells (LMY-920) for Chronic Lymphocytic Leukemia?

Research shows that BAFF CAR-T cells, which target specific receptors on B cells, have been effective in killing various B cell cancers in laboratory and animal studies. This suggests potential effectiveness for treating Chronic Lymphocytic Leukemia, as it is also a B cell cancer. ^{1 2 3 4 5}

What safety data exists for BAFF CAR-T Cells in humans?

BAFF CAR-T cells have been studied for their ability to target and kill B cell cancers, and while they show promise in treating these cancers, the research does not provide specific safety data for humans. However, similar CAR-T cell therapies have been associated with side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage), which are important to consider. ^{5 6 7 8 9}

How is the BAFF CAR-T cell treatment different from other treatments for chronic lymphocytic leukemia?

The BAFF CAR-T cell treatment is unique because it targets three different receptors (BAFF-R, BCMA, and TACI) on B cells, which helps prevent the cancer cells from escaping detection. This approach is different from other treatments that typically target only one receptor, like CD19, and may be less effective if the cancer cells lose that specific marker. ^{2 4 5 6 7}

What is the purpose of this trial?

CAR-T cell treatment of refractory lymphoma has shown success, particularly with CD-19 targeted CAR-T cells, however, many participants are refractory or relapse after response. Responses are more limited in CLL/SLL, possibly secondary to the suppressive effect of circulating B cells on T cell function. BAFF receptor is a target that has been explored in CLL. Preclinical data indicates that CAR- T cells expressing B-cell activating factor (BAFF) can be another effective strategy to treat refractory CLL. This study aims to explore the efficacy of LMY-920 a BAFF-ligand CAR T cells with depletion of B cells with Obinutuzumab prior to apheresis.

Research Team

Paolo Caimi, MD

Principal Investigator

Case Comprehensive Cancer Center, Cleveland Clinic Taussig Cancer Institute

Eligibility Criteria

This trial is for people with Chronic Lymphocytic Leukemia (CLL) or Non-Hodgkin's Lymphoma that hasn't improved after standard treatments. Participants should have enough healthy blood cells and organ function to undergo the therapy. Specific eligibility details are not provided, but typically include age, overall health status, and disease characteristics.

Inclusion Criteria

AST (SGOT)/ALT ≤ 2.5 X institutional upper limit of normal

Total bilirubin ≤ 1.5 X upper institutional limit of normal

I have active CLL or measurable SLL.

Exclusion Criteria

Less than 28 days elapsed between prior treatment with investigational agent(s) and the day of lymphocyte collection

Pregnant or breastfeeding women

Serologic status reflecting active hepatitis B or C infection

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants undergo B cell depletion with Obinutuzumab prior to apheresis

1-2 weeks

Treatment

Participants receive BAFF CAR-T cells (LMY-920) for treatment of relapsed or refractory CLL/SLL

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• BAFF CAR-T Cells (LMY-920)

Trial Overview The study tests a new CAR-T cell therapy called LMY-920 targeting BAFF receptor on cancerous B cells in CLL patients. It includes pre-treatment with Obinutuzumab to deplete B cells before collecting patient's T cells for engineering into CAR-T cells which are then given back to attack the cancer.

Participant Groups

Group I: LMY-920 dose escalation Experimental Treatment 4 Interventions

Who Is Running the Clinical Trial?

Paolo Caimi, MD

Lead Sponsor

Trials

5

Recruited

170+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Findings from Research

In a study of 42 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), those treated with anti-CD19 CAR T cells showed a complete response (CR) rate of 28% and an overall response rate of 44% after 4 weeks, with a median overall survival of 64 months.

Achieving a complete response was linked to significantly longer overall survival and progression-free survival, indicating that the effectiveness of CAR T cell therapy is enhanced in patients who reach CR, regardless of whether they received a low or high dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. Frey, NV., Gill, S., Hexner, EO., et al.[2021]

CAR T-cell therapy has faced challenges in treating chronic lymphocytic leukemia (CLL) due to the immune dysfunction of patient-derived T cells, leading to inferior efficacy compared to other cancers.

New strategies, including novel CAR T-cell formulations like lisocabtagene maraleucel combined with ibrutinib, aim to enhance T-cell quality and functionality, potentially improving treatment outcomes for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep? Vitale, C., Griggio, V., Perutelli, F., et al.[2023]

Chimeric antigen receptor T (CART) cells targeting CD19 show promise in treating chronic lymphocytic leukemia (CLL), but their effectiveness is lower compared to other blood cancers, possibly due to impaired T-cell fitness in CLL patients.

The use of ibrutinib during CART cell production enhances the viability and expansion of CART cells from CLL patients, enriches them with less-differentiated T cell subsets, and improves their functionality by reducing exhaustion markers, suggesting a potential strategy to overcome treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. Fan, F., Yoo, HJ., Stock, S., et al.[2021]

BAFF CAR-T cells, developed using a non-viral gene delivery method, effectively target and kill various B cell cancers, including mantle cell lymphoma, multiple myeloma, and acute lymphoblastic leukemia, both in laboratory settings and in animal models.

These CAR-T cells bind to three different BAFF receptors, which helps reduce the risk of cancer cells escaping treatment by losing the targeted antigen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers. Wong, DP., Roy, NK., Zhang, K., et al.[2023]

The development of BAFF-R CAR T cells shows promise in treating B cell malignancies, effectively targeting tumors even when CD19 expression is lost, which is a common issue with current therapies.

In preclinical models, BAFF-R CAR T cells successfully eradicated established tumors and demonstrated antitumor activity against relapsed cases of acute lymphoblastic leukemia (ALL) that had lost CD19 expression, suggesting a potential solution to tumor relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. Qin, H., Dong, Z., Wang, X., et al.[2020]

CAR-modified T-cell therapy targeting CD19 has shown impressive remission rates of 50% to 60% at 1 year for patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), marking a significant advancement in treatment for this challenging condition.

While the therapy is effective, it can lead to side effects such as cytokine release syndrome (CRS) and neurotoxicity shortly after treatment, as well as long-term B-cell aplasia, which are important considerations for patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL. DiNofia, AM., Maude, SL.[2020]

CAR-T-cell therapy has shown significant promise in treating relapsed or refractory B-cell malignancies, such as B-cell non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia, by targeting specific antigens like CD19 and BCMA.

The review highlights both the efficacy and toxicity of CD19- and BCMA-targeted CAR-T-cell therapies, indicating that while these treatments can be effective, they also come with potential side effects that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Roex, G., Feys, T., Beguin, Y., et al.[2020]

References

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

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. [2021]

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

CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep? [2023]

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

Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. [2021]

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

CARs in chronic lymphocytic leukemia -- ready to drive. [2021]

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

A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers. [2023]

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

CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. [2020]

7. Germany pubmed.ncbi.nlm.nih.gov

Translational development of a novel BAFF-R CAR-T therapy targeting B-cell lymphoid malignancies. [2023]

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

Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL. [2020]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. [2020]