TriPRIL CAR T Cell Therapy for Multiple Myeloma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Marcela V. Maus, M.D.,Ph.D.
Must not be taking: Immunosuppressants, Steroids
Disqualifiers: Active infection, Heart failure, CNS pathology, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing TriPRIL CAR T Cells, a new treatment that uses a patient's own immune cells to fight multiple myeloma that has come back or not responded to other treatments. The treatment involves modifying the patient's T cells to better attack cancer cells. About 18 people will participate, receiving one infusion and being monitored for an extended period. This type of therapy has shown promising results in treating various cancers, including multiple myeloma.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, you cannot have had any systemic treatment for multiple myeloma within 14 days before a key procedure, and certain medications that interfere with the study may need to be stopped. It's best to discuss your specific medications with the trial's principal investigator.
What data supports the effectiveness of the TriPRIL CAR T Cell treatment for multiple myeloma?
Research shows that CAR T-cell therapies targeting multiple antigens, like BCMA and CS1, can effectively attack multiple myeloma cells and improve survival in animal models. This suggests that targeting multiple antigens may enhance the treatment's effectiveness and reduce the chance of relapse.
12345What safety data exists for TriPRIL CAR T Cell Therapy for Multiple Myeloma?
TriPRIL CAR T Cell Therapy, like other CAR T cell therapies, can cause side effects such as cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects require careful management, and strategies like premedication and monitoring are recommended to reduce risks.
678910How is the TriPRIL CAR T Cell treatment different from other treatments for multiple myeloma?
TriPRIL CAR T Cell treatment is unique because it uses a trimeric APRIL-based design to target two antigens, BCMA and TACI, on multiple myeloma cells, which helps prevent the cancer from escaping treatment by losing BCMA. This dual-targeting approach is different from traditional CAR T therapies that focus only on BCMA, making it potentially more effective in preventing relapses.
211121314Eligibility Criteria
This trial is for adults over 18 with relapsed or refractory multiple myeloma who have tried at least three prior treatments, including specific inhibitors and antibodies. They must be in relatively good health (ECOG 0-2), not pregnant, willing to use birth control, and able to consent. People with certain heart conditions, active infections, recent other cancer treatments or stem cell transplants can't join.Inclusion Criteria
I am 18 years old or older.
I am able to care for myself and perform daily activities.
My organs and bone marrow are working well.
+8 more
Exclusion Criteria
I have recovered from previous cancer treatment side effects, except for hair loss or mild nerve issues.
I had a stem cell transplant using my own cells within the last 3 months.
My cancer has spread to my brain or spinal cord.
+19 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Leukapheresis
White blood cells are collected from participants
1 day
1 visit (in-person)
Lymphodepletion
Participants receive 3 days of chemotherapy to decrease the number of lymphocytes
1 week
3 visits (in-person)
Treatment
Participants receive one infusion of TriPRIL CAR T Cells
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
24 months
Every 3 months
Participant Groups
The study tests TriPRIL CAR T Cells designed to treat multiple myeloma that's come back or hasn't responded to treatment. Participants also receive Fludarabine and Cyclophosphamide chemotherapy drugs as part of the process before getting the new therapy.
2Treatment groups
Experimental Treatment
Group I: TriPRIL CAR T Cells-Dose ExpansionExperimental Treatment3 Interventions
Prior to receiving TriPRIL CAR T Cells, participants will undergo two preparatory processes:
* Leukapheresis: On day -8 white blood cells will be collected.
* Lymphodepletion: On days, -5, -4. -3 participants will receive 3 days of chemotherapy to decrease the number of lymphocytes
TriPRIL CAR T Cells will be administered intravenously on day 0 using the respective dose (at or below the Maximum Tolerated Dose-MTD), as determined during the dose escalation part.
Group II: TriPRIL CAR T Cells-Dose EscalationExperimental Treatment3 Interventions
Prior to receiving TriPRIL CAR T Cells, participants will undergo two preparatory processes:
* Leukapheresis: On day -8 white blood cells will be collected.
* Lymphodepletion: On days, -5, -4. -3 participants will receive 3 days of chemotherapy to decrease the number of lymphocytes
TriPRIL CAR T Cells will be administered intravenously on day 0 using a 3+3 dose escalation design
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Massachusetts General Hospital Cancer CenterBoston, MA
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Who Is Running the Clinical Trial?
Marcela V. Maus, M.D.,Ph.D.Lead Sponsor
References
CAR T-Cell Therapy for Multiple Myeloma: A Clinical Practice-Oriented Review. [2023]The emergence of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, including multiple myeloma (MM). Two BCMA-directed CAR T-cell products - idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) - have received US Food and Drug Administration (FDA) approval for patients with relapsed/refractory MM who underwent four or more prior lines of therapy (including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody). Despite producing unprecedented response rates in an otherwise difficult to treat patient population, CAR T-cell therapies are commonly associated with immune-related adverse events (e.g., cytokine release syndrome and neurotoxicity), cytopenias, and infections. Moreover, many patients continue to exhibit relapse post-treatment, with resistance mechanisms yet to be fully understood. Ongoing basic, translational, and clinical research efforts are poised to generate deeper insights into the optimal utilization of these therapies, improve their efficacy, minimize associated toxicity, and identify new target antigens in patients with MM.
Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma. [2022]CAR T-cell therapy for multiple myeloma (MM) targeting B-cell maturation antigen (TNFRSF17; BCMA) induces high overall response rates; however, relapse occurs commonly. Implicated in relapse is a reservoir of MM if cells lacking sufficient BCMA surface expression (antigen escape). We demonstrate that simultaneous targeting of an additional antigen-here, G protein-coupled receptor class-C group-5 member-D (GPRC5D)-can prevent BCMA escape-mediated relapse in a model of MM. To identify an optimal approach, we compare subtherapeutic doses of different forms of dual-targeted cellular therapy. These include (1) parallel-produced and pooled mono-targeted CAR T-cells, (2) bicistronic constructs expressing distinct CARs from a single vector, and (3) a dual-scFv "single-stalk" CAR design. When targeting BCMA-negative disease, bicistronic and pooled approaches had the highest efficacy, whereas for dual-antigen-expressing disease, the bicistronic approach was more efficacious than the pooled approach. Mechanistically, expressing two CARs on a single cell enhanced the strength of CAR T-cell/target cell interactions.
A compound chimeric antigen receptor strategy for targeting multiple myeloma. [2019]Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.
Chimeric Antigen Receptor T Cells for Multiple Myeloma: The Journey So Far-And the Road Ahead. [2022]Despite improvements in effective therapy, multiple myeloma remains incurable, and virtually all patients will face relapsed disease at some point after diagnosis. The prognosis for relapsed myeloma after developing resistance to anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation has been poor; however, the development of immune effector cell therapy with chimeric antigen receptor (CAR) T cells may dramatically improve the outlook for patients, although none of these therapies are approved for MM to date. Herein, we review the development and history of CAR T-cell therapy for multiple myeloma, mechanisms of resistance, and strategies to improve outcomes with CAR T therapy.
Clinical Management of Triple-Class Refractory Multiple Myeloma: A Review of Current Strategies and Emerging Therapies. [2022]Major progress has been made in the upfront treatment of multiple myeloma, but the disease ultimately relapses and leads to death in the vast majority of those afflicted. New treatment strategies and modalities are necessary to treat myeloma in relapse, particularly in cases of triple-refractory status defined by disease progression during or shortly after treatment with immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibody therapy. In this manuscript, we review recent promising developments in the treatment of triple-class refractory myeloma including bispecific antibodies and T cell engagers, chimeric antigen receptor cellular therapies, as well as chemotherapeutics with novel mechanisms of action.
Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies. [2021]In the last few years, monoclonal antibodies (mAbs) such as elotuzumab and daratutumab have brought the treatment of multiple myeloma (MM) into the new era of immunotherapy. More recently, chimeric antigen receptor (CAR) modified T cell, a novel cellular immunotherapy, has been developed for treatment of relapsed/refractory (RR) MM, and early phase clinical trials have shown promising efficacy of CAR T cell therapy. Many patients with end stage RRMM regard CAR T cell therapy as their "last chance" and a "hope of cure". However, severe adverse events (AEs) and even toxic death related to CAR T cell therapy have been observed. The management of AEs related to CAR T cell therapy represents a new challenge, as the pathophysiology is not fully understood and there is still no well-established standard of management. With regard to CAR T cell associated toxicities in MM, in this review, we will provide an overview of experience from clinical trials, pathophysiology, and management strategies.
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.
T-Cell-Based Cellular Immunotherapy of Multiple Myeloma: Current Developments. [2022]T-cell-based cellular therapy was first approved in lymphoid malignancies (B-cell acute lymphoblastic leukemia and large B-cell lymphoma) and expanding its investigation and application both in hematological and non-hematological malignancies. Two anti-BCMA (B cell maturation antigen) CAR (Chimeric Antigen Receptor) T-cell therapies have been recently approved for relapsed and refractory multiple myeloma with excellent efficacy even in the heavily pre-treated patient population. This new therapeutic approach significantly changes our practice; however, there is still room for further investigation to optimize antigen receptor engineering, cell harvest/selection, treatment sequence, etc. They are also associated with unique adverse events, especially CRS (cytokine release syndrome) and ICANS (immune effector cell-associated neurotoxicity syndrome), which are not seen with other anti-myeloma therapies and require expertise for management and prevention. Other T-cell based therapies such as TCR (T Cell Receptor) engineered T-cells and non-genetically engineered adoptive T-cell transfers (Vγ9 Vδ2 T-cells and Marrow infiltrating lymphocytes) are also actively studied and worth attention. They can potentially overcome therapeutic challenges after the failure of CAR T-cell therapy through different mechanisms of action. This review aims to provide readers clinical data of T-cell-based therapies for multiple myeloma, management of unique toxicities and ongoing investigation in both clinical and pre-clinical settings.
Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network. [2023]T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.
From bench to bedside: the history and progress of CAR T cell therapy. [2023]Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.
Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma. [2021]Chimeric antigen receptor (CAR) T cells (CARTs) have shown tremendous potential for the treatment of certain B-cell malignancies, including patients with relapsed/refractory multiple myeloma (MM). Targeting the B-cell maturation antigen (BCMA) has produced the most promising results for CART therapy of MM to date, but not all remissions are sustained. Emergence of BCMA escape variants has been reported under the selective pressure of monospecific anti-BCMA CART treatment. Thus, there is a clinical need for continuous improvement of CART therapies for MM. Here, we show that a novel trimeric APRIL (a proliferation-inducing ligand)-based CAR efficiently targets both BCMA+ and BCMA- MM. Modeled after the natural ligand-receptor pair, APRIL-based CARs allow for bispecific targeting of the MM-associated antigens BCMA and transmembrane activator and CAML interactor (TACI). However, natural ligands as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to adequately trigger T-cell activation. We found that using a trimeric rather than a monomeric APRIL format as the antigen-binding domain enhanced binding to BCMA and TACI and CART activity against MM in vitro and in vivo. Dual-specific, trimeric APRIL-based CAR are a promising therapeutic approach for MM with potential for preventing and treating BCMA escape.
Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. [2022]Despite the significant therapeutic advances provided by immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell proliferation and reduced regulatory T cells in non-human primates at well-tolerated doses. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.
A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. [2020]Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).
CAR T-Cell Therapy in Multiple Myeloma: Mission Accomplished? [2023]BCMA-CAR T-cells are the most potent treatment against multiple myeloma. Here, we review the increasing body of clinical and correlative pre-clinical data that support their inclusion into first-line therapy and sequencing prior to T-cell-engaging antibodies. The ambition to cure multiple myeloma with (BCMA-)CAR T-cells is informed by genomic and phenotypic analysis that assess BCMA expression for patient stratification and monitoring, steadily improving early diagnosis and management of side effects, and advances in rapid, scalable CAR T-cell manufacturing to improve access.