ATLCAR.CD138 T Cells for Multiple Myeloma
Recruiting in Palo Alto (17 mi)
Overseen bySascha Tuchman, MD, MHS
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Waitlist Available
Sponsor: UNC Lineberger Comprehensive Cancer Center
No Placebo Group
Trial Summary
What is the purpose of this trial?The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat subjects with cancers. They both have shown promise, but neither alone has been sufficient to cure most subjects. This study is designed to combine both T cells and antibodies to create a more effective treatment. The treatment that is being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD138 antigen (CAR138 T cells).
In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying the subject's genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD138. This antibody floats around in the blood and can detect and stick to cancer cells called multiple myeloma cells because they have a substance on the outside of the cells called CD138. Anti-CD138 antibodies have been used to treat people with multiple myeloma, but have not been strong enough to cure most subjects. For this study, the anti-CD138 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. Only the part of the antibody that sticks to the multiple myeloma cells is attached to the T cells instead of the entire antibody. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD138 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you must stop all current medications. However, you must stop taking corticosteroids at least 48 hours before lymphodepleting chemotherapy and systemic chemotherapy at least 14 days before lymphodepletion. Radiation therapy should be stopped at least 7 days before lymphodepletion. Please consult with your doctor for specific guidance on other medications.
What data supports the idea that ATLCAR.CD138 T Cells for Multiple Myeloma is an effective treatment?
The available research shows that ATLCAR.CD138 T Cells, a type of treatment for multiple myeloma, have shown promising results. For example, a study using a dual-targeting approach with CD138 and CD38 antigens demonstrated a significant improvement in survival for mice with multiple myeloma, with treated mice living an average of 97 days compared to 31 days for untreated mice. This suggests that ATLCAR.CD138 T Cells can effectively target and fight multiple myeloma cells, offering a potential new option for patients who have not responded to other treatments.
12345What safety data is available for ATLCAR.CD138 T Cells in treating multiple myeloma?
The safety data for CAR T-cell therapies targeting multiple myeloma, including those targeting CD138, indicate that common toxicities include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS). CRS of grades 1-2 occurred in a significant number of patients, with some experiencing grade ≥3. Efforts to improve safety include optimizing CAR design and incorporating safety systems like suicide genes. Dual-antigen targeting, such as CD138/CD38, has shown increased specificity and reduced off-target toxicity, suggesting a potentially safer profile for these therapies.
34678Is the treatment CAR138 T Cells a promising treatment for multiple myeloma?
Yes, CAR138 T Cells are a promising treatment for multiple myeloma. They specifically target cancer cells, showing the ability to eliminate tumor cells effectively in both lab and animal studies. This treatment has shown potential to be a safe and effective option for patients with relapsed or hard-to-treat multiple myeloma.
12389Eligibility Criteria
This trial is for adults over 18 with relapsed or refractory multiple myeloma, who've had at least three prior chemotherapy treatments and are not eligible for or have declined a stem-cell transplant. Participants need to be in stable condition without infections, serious heart issues, or other cancers. They must agree to use contraception if necessary and comply with study procedures.Inclusion Criteria
Not pregnant or breastfeeding
Willing and able to comply with study procedures
No medical condition making the protocol unreasonably hazardous
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Participant Groups
The trial is testing CAR138 T cells, which are the patient's own immune cells modified to target cancer cells more effectively. These special T cells carry a part of an antibody that recognizes and attaches to multiple myeloma cells, potentially enhancing the body's ability to fight this type of cancer.
1Treatment groups
Experimental Treatment
Group I: CAR138 T cellsExperimental Treatment1 Intervention
The first 3 subjects enrolled in the study will receive 5x10\^6 CAR138 T-cells/m\^2 via infusion. The number of cells for the infusion will be increased to 1x10\^7 CAR138 T-cells/m\^2 and then, 2.5x10\^7 CAR138 T-cells/m\^2, 5x10\^7 CAR138 T-cells/m\^2, 1x10\^8 CAR138 T-cells/m\^2 and 2x10\^8 CAR138 T-cells/m\^2 in subsequent cohorts of 3 subjects provided no dose limiting toxicities (DLTs) are observed within 4 weeks of the cell infusion. Cohort enrollment will be staggered, requiring each subject to complete at least 2 weeks of safety monitoring following CAR138 T-cell infusion at the designated dose level for the cohort before another subject is allowed to enroll in the cohort.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Lineberger Comprehensive Cancer Center at University of North CarolinaChapel Hill, NC
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Who Is Running the Clinical Trial?
UNC Lineberger Comprehensive Cancer CenterLead Sponsor
Baylor College of MedicineCollaborator
University Cancer Research Fund at Lineberger Comprehensive Cancer CenterCollaborator
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).
Specific Targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptor T cells Directed against CD38 and CD138. [2023]The success of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells illustrates the potential of this novel therapy for multiple myeloma. Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few multiple myeloma- or plasma cell-specific target antigens. We investigated the feasibility of achieving multiple myeloma specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR).
Treatment of Multiple Myeloma Using Chimeric Antigen Receptor T Cells with Dual Specificity. [2021]Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable successes in fighting B-cell leukemias/lymphomas. Promising response rates are reported in patients treated with B-cell maturation antigen (BCMA) CAR T cells for multiple myeloma. However, responses appear to be nondurable, highlighting the need to expand the repertoire of multiple myeloma-specific targets for immunotherapy and to generate new CAR T cells. Here, we developed a "dual-CAR" targeting two multiple myeloma-associated antigens and explored its safety and efficacy. To reduce the "off-target" toxicity, we used the recognition of paired antigens that were coexpressed by the tumor to induce efficient CAR T-cell activation. The dual-CAR construct presented here was carefully designed to target the multiple myeloma-associated antigens, taking into consideration the distribution of both antigens on normal human tissues. Our results showed that the CD138/CD38-targeted dual CAR (dCAR138-38) elicited a potent anti-multiple myeloma response both in vitro and in vivo NSG mice transplanted with a multiple myeloma cell line and treated with dCAR138-38 showed median survival of 97 days compared with 31 days in the control group treated with mock-lymphocytes. The dCAR138-38 showed increased specificity toward cells expressing both targeted antigens compared with single-antigen-expressing cells and low activity toward primary cells from healthy tissues. Our findings indicated that the dCAR138-38 may provide a potent and safe alternative therapy for patients with multiple myeloma.
Chimeric antigen receptor T cell therapy for multiple myeloma. [2020]Chimeric antigen receptor (CAR) T cell therapy is a new cancer immunotherapy targeting cancer-specific cell surface antigen. CD19-CAR T cells have been already shown to be very effective to B cell leukemia/lymphoma. Now, many researchers are developing CAR T cells for multiple myeloma. CAR T cells targeting B cell maturation antigen (BCMA) showed promising efficacy in early phase clinical trials. We have recently reported that CAR T cells targeting the activated integrin β7 can selectively eradicate MM cells including CD19+ clonotypic B cells and are preparing a clinical trial.
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.
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.
A combination of humanized anti-BCMA and murine anti-CD38 CAR-T cell therapy in patients with relapsed or refractory multiple myeloma. [2022]Chimeric antigen receptor T (CAR-T) cells are a promising approach in hematopoietic malignancies. We evaluated the safety and efficacy of a combination of humanized anti-BCMA and murine anti-CD38 CAR-T cell therapy in patients with relapsed or refractory multiple myeloma (R/RMM). Twenty-two R/RMM patients, with a median age of 56 years and a median number of previous therapies of 8, were included in the study. Both CAR-T cells infusion doses were 2.0 × 106/kg. The overall response rate (ORR) was 90.9%, with 12 patients (54.5%) achieving a strict complete response/complete response (sCR/CR). The 24-month overall survival (OS) rate was 56.6%, and the progression-free survival (PFS) rate was 48.7%. Cytokine release syndrome (CRS) of grades 1-2 occurred in 16 patients (72.7%) and of grade ≥3 in six patients (27.3%). Immune effector cell-associated neurotoxic syndrome (ICANS) of grades 1-2 occurred in three patients (13.6%). The combination therapy is potential in R/RMM patients.Trial registration: The patients were enrolled in clinical trials registered as ChiCTR1800017051.
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).
Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma. [2020]After unprecedented successes in B-cell malignancies, chimeric antigen receptor T cells have recently been investigated for the treatment of multiple myeloma. Chimeric antigen receptor targeting T cells B-cell maturation antigen (BCMA) on malignant plasma cells have led to impressive clinical responses in recent trials. However, BCMA-negative relapses have been observed, supporting the need for complementary treatment strategies. Here, we explored the feasibility of targeting CD138 (syndecan-1), a surface marker expressed on both normal and malignant plasma cells. We showed that T cells from both healthy donors and from multiple myeloma patients, when transduced with a CD138-specific chimeric antigen receptor, can eliminate tumor cell lines and primary myeloma cells both in vitro and in vivo. CD138 is also expressed by putative myeloma stem cells identified by Hoechst staining, and these cells can be eliminated by CD138-specific chimeric antigen receptor T cells. Preclinical analyses did not identify any on target off tumor cytotoxicity against normal epithelial or endothelial cells, further supporting the rationale for the use of adoptively transferred CD138-specific chimeric antigen receptor T cells for the treatment of patients with relapsed/refractory multiple myeloma.