CAR-T Cell Therapy for Multiple Myeloma
(LMY-920-002 Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Luminary Therapeutics
Must not be taking: Immunosuppressants, others
Disqualifiers: CNS involvement, Active infection, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
Since CAR-T cell treatment of refractory myeloma has shown success, based on preclinical data, we posit that CAR-T cells expressing B-cell activating factor (BAFF) can become another strategy to treat refractory myeloma, even after relapse following BCMA targeting CAR-T cell treatment. This will be phase 1 study of BAFF ligand CAR-T cells in relapsed and refractory myeloma.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, it mentions that more than 28 days must have passed since any prior treatment with investigational agents before lymphocyte collection, which might imply a need to pause certain treatments. It's best to discuss your specific medications with the trial coordinators.
What data supports the effectiveness of the treatment Autologous CAR-T cell therapy expressing the BAFF-ligand for multiple myeloma?
What safety data exists for CAR-T cell therapy in humans?
CAR-T cell therapy has shown manageable safety concerns, including cytokine-release syndrome (a condition where the immune system releases too many proteins into the blood too quickly), different types of cytopenia (low blood cell counts), infections, and neurotoxicity (nerve damage). Efforts are being made to improve safety, such as incorporating a suicide gene safety system to control the therapy if needed.34678
How is the BAFF-ligand CAR-T cell treatment different from other treatments for multiple myeloma?
This treatment is unique because it uses a special type of immune cell called CAR-T cells that are engineered to target three specific receptors (BAFF-R, BCMA, and TACI) on cancer cells, which helps prevent the cancer from escaping treatment. This approach is different from other treatments that typically target only one receptor.12569
Eligibility Criteria
This trial is for adults over 18 with myeloma that's come back or hasn't responded after at least three treatments, including specific drugs. They must have measurable disease, be in relatively good health (ECOG ≤ 2), and not pregnant or breastfeeding. Participants need functioning major organs and can't have had certain other cancers or heart, lung, liver problems.Inclusion Criteria
My heart pumps well and I don't have fluid around it.
My oxygen level is 92% or higher without extra oxygen.
I agree to not have sex or use birth control and not donate sperm.
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Exclusion Criteria
I have another cancer that needs treatment through the bloodstream.
Less than 28 days elapsed between prior treatment with investigational agent(s) and the day of lymphocyte collection.
I have an autoimmune disease and needed strong medication for it within the last 6 months.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive dose-escalation treatment with BAFF ligand CAR-T cells (LMY-920) to determine the maximum tolerated dose
24 months
Follow-up
Participants are monitored for safety, effectiveness, and response rates after treatment
24 months
Treatment Details
Interventions
- Autologous CAR-T cell therapy expressing the BAFF-ligand (CAR T-cell Therapy)
Trial OverviewThe study tests a new CAR-T cell therapy using BAFF-ligand on patients whose myeloma has relapsed or is refractory to treatment. It's an early-phase trial to see how well these modified immune cells work against cancer that didn’t respond to previous therapies like BCMA targeting CAR-T cells.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: LMY-920 dose escalationExperimental Treatment1 Intervention
Open label, dose escalation study with up to four dose levels of LMY-920. The maximum tolerated dose (MTD) of LMY-920 will be determined using dose-escalation 3+3 design.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University Hospitals Seidman Cancer CenterCleveland, OH
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Who Is Running the Clinical Trial?
Luminary TherapeuticsLead Sponsor
The Cleveland ClinicCollaborator
Case Western Reserve UniversityCollaborator
References
CARs in the Lead Against Multiple Myeloma. [2018]The recent clinical success of CD19-directed chimeric antigen receptor (CAR) T cell therapy in chronic and acute leukemia has led to increased interest in broadening this technology to other hematological malignancies and solid tumors. Now, advances are being made using CAR T cell technology to target myeloma antigens such as B cell maturation antigen (BCMA), CD138, and kappa-light chain as well as CD19 on putative myeloma stem cells. To date, only a limited number of multiple myeloma patients have received CAR T cell therapy but preliminary results have been encouraging. In this review, we summarize the recently reported results of clinical trials conducted utilizing CAR T cell therapy in multiple myeloma (MM).
A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers. [2023]B cell-activating factor (BAFF) binds the three receptors BAFF-R, BCMA, and TACI, predominantly expressed on mature B cells. Almost all B cell cancers are reported to express at least one of these receptors. Here we develop a BAFF ligand-based chimeric antigen receptor (CAR) and generate BAFF CAR-T cells using a non-viral gene delivery method. We show that BAFF CAR-T cells bind specifically to each of the three BAFF receptors and are effective at killing multiple B cell cancers, including mantle cell lymphoma (MCL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL), in vitro and in vivo using different xenograft models. Co-culture of BAFF CAR-T cells with these tumor cells results in induction of activation marker CD69, degranulation marker CD107a, and multiple proinflammatory cytokines. In summary, we report a ligand-based BAFF CAR-T capable of binding three different receptors, minimizing the potential for antigen escape in the treatment of B cell cancers.
Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. [2021]Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma.
Development of CAR-T cell therapies for multiple myeloma. [2021]Currently available data on chimeric antigen receptor (CAR)-T cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated multiple myeloma (MM) patients. The CAR-T field in MM is rapidly evolving with >50 currently ongoing clinical trials across all phases, different CAR-T design, or targets. Most of the CAR-T trials are performed in China and the United States, while European centers organize or participate in only a small fraction of current clinical investigations. Autologous CAR-T cell therapy against B cell maturation antigen shows the best evidence of efficacy so far but main issues remain to be addressed: duration of response, longer follow-up, prolonged cytopenia, patients who may benefit the most such as those with extramedullary disease, outcome prediction, and the integration of CAR-T cell therapy within the MM treatment paradigm. Other promising targets are, i.a.,: CD38, SLAMF7/CS1, or GPRC5D. Although no product has been approved to date, cost and production time for autologous products are expected to be the main obstacles for broad use, for which reason allogeneic CAR-T cells are currently explored. However, the inherent risk of graft-versus-host disease requires additional modification which still need to be validated. This review aims to present the current status of CAR-T cell therapy in MM with an overview on current targets, designs, and stages of CAR-T cell development. Main challenges to CAR-T cell therapy will be highlighted as well as strategies to structurally improve the CAR-T cell product, and thereby its efficacy and safety. The need for comparability of the most promising therapies will be emphasized to balance risks and benefits in an evidence-based but personalized approach to further improve outcome of patients with MM.
Long-Term Follow-Up of Combination of B-Cell Maturation Antigen and CD19 Chimeric Antigen Receptor T Cells in Multiple Myeloma. [2022]A combination of anti-B-cell maturation antigen (BCMA) and anti-CD19 chimeric antigen receptor (CAR) T cells induced high response rates in patients with relapsed or refractory (R/R) multiple myeloma (MM), but long-term outcomes have not been assessed yet.
Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma. [2020]Multiple myeloma (MM), considered an incurable hematological malignancy, is characterized by its clonal evolution of malignant plasma cells. Although the application of autologous stem cell transplantation (ASCT) and the introduction of novel agents such as immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have doubled the median overall survival to eight years, relapsed and refractory diseases are still frequent events in the course of MM. To achieve a durable and deep remission, immunotherapy modalities have been developed for relapsed/refractory multiple myeloma (RRMM). Among these approaches, chimeric antigen receptor (CAR) T-cell therapy is the most promising star, based on the results of previous success in B-cell neoplasms. In this immunotherapy, autologous T cells are engineered to express an artificial receptor which targets a tumor-associated antigen and initiates the T-cell killing procedure. Tisagenlecleucel and Axicabtagene, targeting the CD19 antigen, are the two pacesetters of CAR T-cell products. They were approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). Their development enabled unparalleled efficacy in combating hematopoietic neoplasms. In this review article, we summarize six promising candidate antigens in MM that can be targeted by CARs and discuss some noteworthy studies of the safety profile of current CAR T-cell therapy.
CAR T-cell therapy for multiple myeloma: state of the art and prospects. [2021]Chimeric antigen receptors (CAR) are fusion proteins containing an antigen-recognition domain coupled to a T-cell activation domain (eg, CD3ζ [CD247]) and to a costimulatory domain (eg, CD28 or 4-1BB [TNFRSF9, also known as CD137]). The B-cell maturation antigen (BCMA; TNFRSF17) is an attractive target for CAR T-cell therapy because it is only expressed by normal and malignant plasma cells and by a subset of mature B cells. Several trials of anti-BCMA CAR T cells have shown high-quality responses, including minimal residual disease-negativity in patients with multiple myeloma who were heavily pretreated. Phase 3 trials are currently evaluating CAR T-cell therapy versus standard-of-care regimens in patients in earlier stages of the disease. Trials are also ongoing in newly diagnosed patients with high-risk cytogenetic profiles or with residual disease after transplantation. CAR T cells targeting other multiple myeloma antigens, such as CD19, CD38, CD138 (SYND1), and SLAMF7, are also being explored. Toxicities associated with CAR T cells include cytokine-release syndrome, different types of cytopenia, infections, and neurotoxicity. Although some subsets of patients have sustained responses for more than 1 year, most patients eventually relapse, which might be related to the loss of CAR T cells, loss of antigen expression on the tumour cell surface, or to an immunosuppressive microenvironment that impairs the activity of T cells. Efforts to improve the effectiveness of CAR T-cell therapy include optimising CAR design and adapting the manufacturing process to generate cell products enriched for specific subsets of T cells (eg, early memory cells). Other strategies explored in trials include dual-antigen targeting to prevent antigen escape and rational combination therapy to enhance persistence. Several approaches are also being developed to improve the safety of CAR T-cell therapy, such as the incorporation of a suicide gene safety system.
CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide. [2021]Multiple myeloma (MM) is a plasma cell malignancy and most patients eventually succumb to the disease. Chimeric antigen receptor (CAR) T cells targeting B-Cell Maturation Antigen (BCMA) on MM cells have shown high-response rates, but limited durability. CD229/LY9 is a cell surface receptor present on B and T lymphocytes that is universally and strongly expressed on MM plasma cells. Here, we develop CD229 CAR T cells that are highly active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells. We do not observe fratricide during CD229 CAR T cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM.
sBCMA Plasma Level Dynamics and Anti-BCMA CAR-T-Cell Treatment in Relapsed Multiple Myeloma. [2023]Novel chimeric antigen receptor T-cells (CAR-T) target the B-cell maturation antigen (BCMA) expressed on multiple myeloma cells. Assays monitoring CAR-T cell expansion and treatment response are being implemented in clinical routine.