Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Sorrento Therapeutics, Inc.
No Placebo Group
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?This trial tests a new drug called STI-1492 for patients whose multiple myeloma has returned or not responded to other treatments. The drug is given through an IV, and the dose is gradually increased to find the safest and most effective amount.
Is the treatment STI-1492 a promising treatment for multiple myeloma?Yes, STI-1492, which is a type of CAR-T cell therapy targeting CD38, shows promise for treating multiple myeloma. It has been shown to effectively target and kill cancer cells in the lab and in animal studies. This treatment uses the body's own immune cells to fight the cancer, making it a promising new approach for patients with multiple myeloma.13479
What safety data is available for Anti-CD38 A2 DAR T Cells in treating multiple myeloma?The safety data for Anti-CD38 A2 DAR T Cells, also known as STI-1492 or CD38 DAR-T therapy, indicates that these cells have shown effective anti-tumor activity against multiple myeloma with some cytotoxicity towards CD38-positive nonmalignant cells. Studies have demonstrated that CD38 CAR-T cells can effectively target and kill CD38-positive tumor cells, but they may also affect CD38-positive fractions of T cells, B cells, and natural killer cells. However, the therapy did not completely inhibit the development of colony-forming units from CD34+ hematopoietic progenitor cells. Additionally, the use of a caspase-9-based suicide gene has been suggested to control undesired effects. Overall, the therapy shows promise with a need for strategies to minimize off-target effects.23678
What data supports the idea that Anti-CD38 A2 DAR T Cells for Multiple Myeloma is an effective treatment?The available research shows that Anti-CD38 A2 DAR T Cells are effective in treating multiple myeloma. These cells are designed to target and kill cancer cells that express a protein called CD38, which is common in multiple myeloma. Studies have shown that these T cells can effectively kill cancer cells in lab experiments and in animal models. They also produce substances that help destroy the cancer cells. Compared to other treatments, these T cells specifically target the cancer cells without harming many other types of cells, making them a promising option for treating multiple myeloma.23578
Do I need to stop my current medications to join the trial?The trial requires that you stop any systemic therapy for multiple myeloma at least 14 days before starting the study dose. If you've had cellular therapy, it must be at least 8 weeks prior. The protocol does not specify other medications, but you should discuss your current medications with the study team.
Eligibility Criteria
This trial is for adults with relapsed or refractory multiple myeloma who've had previous treatments, can follow the study plan and contraception rules, have CD38 expression in their cancer cells, a life expectancy of at least 12 weeks, measurable disease levels, and good oxygen levels without assistance.Inclusion Criteria
My multiple myeloma has returned or didn't respond after treatment.
My cancer shows CD38 on the cell surface.
Exclusion Criteria
I have active plasma cell leukemia.
I have had cancer spread to my brain or spine.
My heart's pumping ability is below 40%.
I haven't had any systemic therapy for my multiple myeloma in the last 14 days.
My blood clotting tests are abnormal, but I am on a stable dose of blood thinner.
I have HIV/AIDS or chronic hepatitis B or C.
I do not have any major health or mental issues preventing me from joining the study.
I have another cancer besides multiple myeloma that is either not in remission or was treated in the last 3 years.
I currently have an infection.
I had a stem cell transplant less than 6 months ago, have GvHD, or am on immunosuppressants.
I have a tumor outside of my bone marrow.
I have no lasting side effects from cancer treatment worse than Grade 2.
I need help with my daily activities due to my health condition.
Treatment Details
The trial tests STI-1492, an experimental therapy involving anti-CD38 T cells. It's given once through the vein to see how safe it is and what dose works best for people whose multiple myeloma has come back or didn't respond to treatment.
1Treatment groups
Experimental Treatment
Group I: STI-1492Experimental Treatment1 Intervention
Four dosing cohorts will be evaluated: Cohort 1 (1 × 10\^5 donor DAR-T cells/kg); Cohort 2 (5 × 10\^5 donor DAR-T cells/kg); Cohort 3 (1 × 10\^6 donor DAR-T cells/kg); Cohort 4 (3 × 10\^6 donor DAR-T cells/kg) where STI-1492 will be administered intravenously once.
STI-1492 is already approved in United States for the following indications:
🇺🇸 Approved in United States as STI-1492 for:
- Relapsed or Refractory Multiple Myeloma
Find a clinic near you
Research locations nearbySelect from list below to view details:
University of OklahomaOklahoma City, OK
UC IrvineOrange, CA
UC DavisSacramento, CA
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Who is running the clinical trial?
Sorrento Therapeutics, Inc.Lead Sponsor
References
Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. [2021]Myeloma plasma cells constitute 10% to 90% of the total bone marrow cell count in patients with multiple myeloma (MM). These cells express a variety of cell surface markers, such as HLA-ABC and HLA-DR, and surface antigens that are necessary for professional antigen-presenting cells, including adhesion and costimulatory molecules. In this study, we examined the expression of major histocompatability complex (MHC) and costimulatory molecules on CD38(bright,++) plasma cells in bone marrow aspirates from eight MM patients. Small percentages of plasma cells expressed weak but detectable levels of HLA-DR, HLA-DQ, CD40, CD80, and CD86, which could be upregulated by interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha. CD38++ plasma cell and CD38(dim,+) cells were sorted from freshly isolated bone marrow mononuclear cells and tested for their capacity to act as antigen-presenting cells. Indeed, both CD38++ plasma cells and CD38+ cells were able to stimulate allogeneic T cells and present the soluble antigens purified protein derivative and tetanus toxoid to autologous T cells. Recognition of the antigens led to T-cell proliferation and secretion of IFN-gamma and was MHC class-I and -II restricted. Antigen processing and presentation by CD38++ and CD38+ cells were abolished by treatment of the cells with chloroquine. Hence, our study provides for the first time evidence that myeloma plasma cells may act as antigen-presenting cells. Further studies are warranted to examine in detail the molecules required for inducing T-cell stimulation.
Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. [2018]Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite becoming CD38-negative during culture. CD38-chimeric antigen receptor-transduced T cells also displayed significant anti-tumor effects in a xenotransplant model, in which multiple myeloma tumors were grown in a human bone marrow-like microenvironment. CD38-chimeric antigen receptor-transduced T cells also appeared to lyse the CD38(+) fractions of CD34(+) hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells but did not inhibit the outgrowth of progenitor cells into various myeloid lineages and, furthermore, were effectively controllable with a caspase-9-based suicide gene. These results signify the potential importance of CD38-chimeric antigen receptor-transduced T cells as therapeutic tools for CD38(+) malignancies and warrant further efforts to diminish the undesired effects of this immunotherapy using appropriate strategies.
Anti-Multiple Myeloma Activity of Nanobody-Based Anti-CD38 Chimeric Antigen Receptor T Cells. [2019]Chimeric antigen receptor T cells (CAR-Ts) are a promising strategy for the treatment of many cancers, including multiple myeloma (MM), a hematological malignancy characterized by the high expression of CD38. To broaden the applications of using CD38 as a therapeutic target for the disease, we developed a new nanobody against CD38 and constructed a CD38-CAR that was composed of this nanobody as the targeting domain, and 4-1BB and CD3ζ as the costimulatory and activating domains, in a lentiviral vector. CD3+ T cells from healthy individuals were transduced with the CD38-CAR at an efficiency higher than 60%, as determined by CD38-CAR expression using flow cytometry. The CD38-CAR-Ts proliferated efficiently and produced more inflammatory cytokines, such as IL-2, IFN-γ, and TNF-α, when activated. The CD38-CAR-Ts effectively lysed CD38+ MM cell lines, including LP-1, RPMI 8226, OPM2, and MOLP8, and primary MM cells from multiple myeloma patients. The specificity was demonstrated by the fact that CD38-CAR-Ts showed little cytotoxicity on LP-1 cells with CD38 knocked out or on K562 cells, which do not express CD38. CD38-CAR-Ts appeared to have a very slight cytotoxicity against CD38+ fractions of T cells, B cells, and natural killer cells. In addition, the lysis of CD34+ hematopoietic progenitor cells did not completely inhibit the development of colony-forming units. In vivo, CD38-CAR-Ts inhibited tumor growth in NOD/SCID mice that were subcutaneously inoculated with RPMI 8226 cells. These results demonstrate that the CD38-CAR-Ts constructed with the anti-CD38 nanobody are a promising approach for the treatment of multiple myeloma.
CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma. [2020]Multiple Myeloma (MM) is a hematological cancer characterized by proliferation of malignant plasma cells in the bone marrow (BM). MM represents the second most frequent hematological malignancy, accounting 1% of all cancer and 13% of hematological tumors, with ~9,000 new cases per year. Patients with monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic smoldering MM (SMM) usually evolve to active MM in the presence of increased tumor burden, symptoms and organ damage. Despite the role of high dose chemotherapy in combination with autologous stem cell transplantation and the introduction of new treatments, the prognosis of MM patients is still poor, and novel therapeutic approaches have been tested in the last years, including new immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies (mAbs). CD38 is a glycoprotein with ectoenzymatic functions, which is expressed on plasma cells and other lymphoid and myeloid cell populations. Since its expression is very high and uniform on myeloma cells, CD38 is a good target for novel therapeutic strategies. Among them, immunotherapy represents a promising approach. Here, we summarized recent findings regarding CD38-targeted immunotherapy of MM in pre-clinical models and clinical trials, including (i) mAbs (daratumumab and isatuximab), (ii) radioimmunotherapy, and (iii) adoptive cell therapy, using chimeric antigen receptor (CAR)-transfected T cells specific for CD38. Finally, we discussed the efficacy and possible limitations of these therapeutic approaches for MM patients.
Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell-recruiting Antibody Optimized for Cytotoxicity and Cytokine Release. [2020]Despite advances in the treatment of multiple myeloma, new therapies are needed to induce more profound clinical responses. T-cell-redirected lysis triggered by bispecific antibodies recruiting T cells to cancer cells is a clinically validated mechanism of action against hematologic malignancies and CD38 is a tumor-associated antigen with near-universal expression in multiple myeloma. Thus, an anti-CD38/CD3 bispecific T-cell-recruiting antibody has the potential to be an effective new therapeutic for multiple myeloma.
CD38-specific Chimeric Antigen Receptor Expressing Natural Killer KHYG-1 Cells: A Proof of Concept for an "Off the Shelf" Therapy for Multiple Myeloma. [2021]Chimeric antigen receptor (CAR) T cells are highly successful in the treatment of hematologic malignancies. We recently generated affinity-optimized CD38CAR T cells, which effectively eliminate multiple myeloma (MM) cells with little or no toxicities against nonmalignant hematopoietic cells. The lack of universal donors and long manufacturing times however limit the broad application of CAR T cell therapies. Natural killer (NK) cells generated from third party individuals may represent a viable source of "off the shelf" CAR-based products, as they are not associated with graft-versus-host disease unlike allogeneic T cells. We therefore explored the preclinical anti-MM efficacy and potential toxicity of the CD38CAR NK concept by expressing affinity-optimized CD38CARs in KHYG-1 cells, an immortal NK cell line with excellent expansion properties. KHYG-1 cells retrovirally transduced with the affinity-optimized CD38CARs expanded vigorously and mediated effective CD38-dependent cytotoxicity towards CD38high MM cell lines as well as primary MM cells ex vivo. Importantly, the intermediate affinity CD38CAR transduced KHYG-1 cells spared CD38neg or CD38int nonmalignant hematopoietic cells, indicating an optimal tumor nontumor discrimination. Irradiated, short living CD38CAR KHYG-1 cells also showed significant anti-MM effects in a xenograft model with a humanized bone marrow-like niche. Finally, CD38CAR KHYG-1 cells effectively eliminated primary MM cells derived from patients who are refractory to CD38 antibody daratumumab. Taken together, the results of this proof-of-principle study demonstrate the potential value of engineering affinity-optimized CD38CARs in NK cells to establish effective anti-MM effects, with an excellent safety profile, even in patients who failed to response to most advanced registered myeloma therapies, such as daratumumab.
Characterization of the Therapeutic Effects of Novel Chimeric Antigen Receptor T Cells Targeting CD38 on Multiple Myeloma. [2021]Multiple myeloma (MM) is a tumor type characterized by the unregulated proliferation of clonal plasma cells in the bone marrow. Immunotherapy based on chimeric antigen receptor T cell (CAR-T) therapy has achieved exciting success in the treatment of hematological malignant tumors. CD38 is highly and evenly expressed in MM and is an attractive target for MM treatment. Here, we successfully constructed two novel second-generation CAR-T cells targeting CD38 by retroviral vector transduction. CD38 CAR-T cells could be activated effectively after stimulation with CD38-positive tumor cells and secrete cytokines such as IFN-γ and TNF-α to promote tumor cell apoptosis in in vitro experiments. Real-time fluorescence monitoring experiments, luciferase detection experiments and flow cytometry experiments revealed the efficient and specific killing abilities of CD38 CAR-T cells against CD38-positive tumor cells. The proliferation ability of CD38 CAR-T cells in vitro was higher than that of untransduced T cells. Further antitumor experiments in vivo showed that CD38 CAR-T cells could be quickly activated to secrete IFN-γ and eliminate tumors. Thus, novel CD38-targeted second-generation CAR-T cells have efficient and specific antitumor activity and may become a novel therapy for the clinical treatment of MM.
Challenges in αCD38-chimeric antigen receptor (CAR)-expressing natural killer (NK) cell-based immunotherapy in multiple myeloma: Harnessing the CD38dim phenotype of cytokine-stimulated NK cells as a strategy to prevent fratricide. [2023]Label="BACKGROUND AIMS">Adoptive cell therapy with chimeric antigen receptor (CAR)-expressing natural killer (NK) cells is an emerging approach that holds promise in multiple myeloma (MM). However, the generation of CAR-NK cells targeting CD38 is met with obstacles due to the expression of CD38 on NK cells. Knock-out of CD38 is currently explored as a strategy, although the consequences of the lack of CD38 expression with regards to engraftment and activity in the bone marrow microenvironment are not fully elucidated. Here, we present an alternative approach by harnessing the CD38dim phenotype occurring during long-term cytokine stimulation of primary NK cells.
Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma. [2023]CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.