CAR T-Cell Therapy for Leukemia
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: St. Jude Children's Research Hospital
No Placebo Group
Approved in 2 jurisdictions
Trial Summary
What is the purpose of this trial?This is a Phase I clinical study evaluating the safety and maximum tolerated dose of a novel CAR T-cell product: allogeneic memory (CD45RA- negative) T-cells expressing a CD19-specific CAR 41BBz (CD19-CAR.CD45RA- negative T-cells) for the treatment of patients ≤ 21 years old with relapsed and/ or refractory CD19-positive leukemia.
Primary Objective
To determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with allogeneic CD19-CAR.CD45RA-negative T-cells in pediatric, adolescent and young adult patients ≤ 21 years of age, with relapsed and/or refractory CD19-positive leukemia.
Secondary Objectives
* To evaluate the anti-leukemic activity of allogeneic CD19-CAR.CD45RA-negative T-cells.
* To determine rates and severity of graft-versus-host-disease (GVHD) after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells.
Exploratory Objectives
* To study the expansion, persistence and phenotype of allogeneic CD19-CAR.CD45RA-negative T-cells.
* To characterize the cytokine profile in the peripheral blood and CSF after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells.
* To assess whether allogeneic CD19-CAR.CD45RA-negative T-cells acquire functional versus exhaustion-associated epigenetic programs.
* To determine immune reconstitution post treatment, and the clonal structure and endogenous repertoire of allogeneic CD19-CAR.CD45RA-negative T-cells and relate inferred specificity to CAR response profiles.
* To characterize incidence and mechanisms of relapse post-therapy with allogeneic CD19-CAR.CD45RA-negative T-cells.
Is CAR T-cell therapy generally safe for humans?
CAR T-cell therapy, including CD19-specific CAR T-cells, has shown promise in treating certain blood cancers, but it can cause serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are significant but can often be managed with medical care. Cardiovascular issues like irregular heartbeats and low blood pressure have also been reported, but more research is needed to fully understand these risks.
567912How is the CAR T-Cell Therapy for Leukemia treatment different from other treatments?
This treatment uses donor-derived memory T-cells that are engineered to target CD19, which is different from traditional autologous CAR T-cell therapies that use the patient's own cells. This approach can be beneficial for patients who cannot produce their own CAR T-cells due to T-cell dysfunction.
2481113What data supports the effectiveness of the treatment CD19-CAR T-cells for leukemia?
Research shows that CD19-CAR T-cell therapy can lead to complete remission in patients with certain types of leukemia, such as B-cell acute lymphoblastic leukemia (B-ALL). However, while initial remission rates are high, maintaining long-term remission can be challenging, with some patients experiencing relapse.
1341014Will I have to stop taking my current medications?
The trial protocol suggests that you may need to stop certain medications. Specifically, you should not be on systemic steroids exceeding a certain dose or any systemic therapy that might interfere with the CAR T-cell product within 14 days before the infusion. Additionally, intrathecal chemotherapy should not be taken within 7 days prior to the infusion.
Eligibility Criteria
This trial is for young patients (≤ 21 years old) with relapsed or refractory CD19-positive leukemia who haven't responded to previous treatments and are not suitable for autologous CD19-CAR T-cell therapy. They should have a matched family member donor, good heart, kidney, liver function, no severe infections or significant arrhythmias, and must agree to birth control if sexually active.Inclusion Criteria
I can do most activities but may need help.
My condition relapsed after a stem cell transplant from a donor.
I am not a candidate for a specific type of cell therapy.
My leukemia tests positive for CD19.
My condition has not improved despite treatment.
My condition has worsened after initial improvement.
My liver enzymes are within 5 times the normal limit.
I haven't taken high doses of steroids within the last week.
My lung function is at least half of what is expected, or my oxygen levels are good without extra oxygen.
I have never been diagnosed with HIV.
My leukemia has returned or is not responding to treatment and tests positive for CD19.
I have not had a stem cell transplant from the same donor as my CAR T-cell therapy.
I have received a stem cell transplant from the same donor as my CAR T-cell therapy.
My condition has worsened or returned for at least the second time.
I do not have leukemia in my brain causing symptoms.
I am 18 years old or older.
I do not have any severe, uncontrolled infections.
My heart pumps well enough, meeting the minimum required efficiency.
I have had a failed attempt at collecting my own stem cells.
My condition did not improve after receiving additional treatment.
I have a family member who is at least a half match for organ or tissue donation.
I have been approved as a donor according to the required health regulations.
My kidney function is within the required range for my age.
I am 21 years old or younger.
My condition worsened or didn't improve after CD19-CAR T-cell therapy.
I am ineligible for a stem cell transplant as part of my first relapse treatment.
I have had a failed attempt at making CAR T-cells from my own cells.
My cancer did not respond to at least 2 rounds of strong chemotherapy.
Exclusion Criteria
Not applicable.
Participant Groups
The study tests the safety and maximum tolerated dose of allogeneic memory T-cells expressing a CD19-specific CAR in children and young adults with leukemia. It aims to find out how well these cells work against leukemia without causing graft-versus-host disease.
2Treatment groups
Experimental Treatment
Group I: Group BExperimental Treatment6 Interventions
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
Group II: Group AExperimental Treatment6 Interventions
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
CD19-CAR(Mem) T-cells is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as CD19-CAR T-cells for:
- Relapsed/Refractory CD19-positive leukemia
🇪🇺 Approved in European Union as CD19-CAR T-cells for:
- Relapsed/Refractory CD19-positive leukemia
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
St. Jude Children's Research HospitalMemphis, TN
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Who is running the clinical trial?
St. Jude Children's Research HospitalLead Sponsor
References
Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. [2023]The adoptive transfer of donor T cells that have been genetically modified to recognize leukemia could prevent or treat leukemia relapse after allogeneic HSCT (allo-HSCT). However, adoptive therapy after allo-HSCT should be performed with T cells that have a defined endogenous TCR specificity to avoid GVHD. Ideally, T cells selected for genetic modification would also have the capacity to persist in vivo to ensure leukemia eradication. Here, we provide a strategy for deriving virus-specific T cells from CD45RA(-)CD62L(+)CD8(+) central memory T (T(CM)) cells purified from donor blood with clinical grade reagents, and redirect their specificity to the B-cell lineage marker CD19 through lentiviral transfer of a gene encoding a CD19-chimeric Ag receptor (CAR). Virus-specific T(CM) were selectively transduced by exposure to the CD19 CAR lentivirus after peptide stimulation, and bi-specific cells were subsequently enriched to high purity using MHC streptamers. Activation of bi-specific T cells through the CAR or the virus-specific TCR elicited phosphorylation of downstream signaling molecules with similar kinetics, and induced comparable cytokine secretion, proliferation, and lytic activity. These studies identify a strategy for tumor-specific therapy with CAR-modified T cells after allo-HSCT, and for comparative studies of CAR and TCR signaling.
Adoptive T-cell therapy for Leukemia. [2023]Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies. Over the past few decades, many leukemia antigens have been discovered that can separate malignant cells from normal host cells and render them vulnerable targets. In concert, the field of T-cell engineering has matured to enable transfer of ectopic high-affinity antigen receptors into host or donor cells with greater efficiency and potency. Many preclinical studies have demonstrated that engineered and conventional T-cells can mediate lysis and eradication of leukemia via one or more leukemia antigen targets. This evidence now serves as a foundation for clinical trials that aim to cure leukemia using T-cells. The recent clinical success of anti-CD19 chimeric antigen receptor (CAR) cells for treating patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia displays the potential of this new therapeutic modality. In this review, we discuss some of the most promising leukemia antigens and the novel strategies that have been implemented for adoptive cellular immunotherapy of lymphoid and myeloid leukemias. It is important to summarize the data for ACT of leukemia for physicians in-training and in practice and for investigators who work in this and related fields as there are recent discoveries already being translated to the patient setting and numerous accruing clinical trials. We primarily focus on ACT that has been used in the clinical setting or that is currently undergoing preclinical testing with a foreseeable clinical endpoint.
Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. [2022]Administration of lymphodepletion chemotherapy followed by CD19-specific chimeric antigen receptor (CAR)-modified T cells is a remarkably effective approach to treating patients with relapsed and refractory CD19(+) B-cell malignancies. We treated 7 patients with B-cell acute lymphoblastic leukemia (B-ALL) harboring rearrangement of the mixed lineage leukemia (MLL) gene with CD19 CAR-T cells. All patients achieved complete remission (CR) in the bone marrow by flow cytometry after CD19 CAR-T-cell therapy; however, within 1 month of CAR-T-cell infusion, 2 of the patients developed acute myeloid leukemia (AML) that was clonally related to their B-ALL, a novel mechanism of CD19-negative immune escape. These reports have implications for the management of patients with relapsed and refractory MLL-B-ALL who receive CD19 CAR-T-cell therapy.
Allogeneic CAR19 cells clear ALL. [2021]Chimeric antigen receptor T cells redirected to CD19 (chimeric antigen receptor [CAR19]) show great promise in the clinic to treat refractory CD19+ acute lymphoblastic leukemia (ALL). However, production of autologous CAR19 cells from these patients can be difficult as patients frequently have T-cell dysfunction, due to disease and/or treatment-related effects. In this issue of Blood, Jacoby et al1 addressed this by exploring whether allogeneic donor CAR19 cells could be used to treat ALL-bearing mice using a minor mismatch bone marrow transplant model.
Chimeric Antigen Receptor T-Cell Therapy for the Community Oncologist. [2021]: The field of cancer immunotherapy has rapidly progressed in the past decade as several therapeutic modalities have entered into the clinic. One such immunotherapy that has shown promise in the treatment of cancer is the use of chimeric antigen receptor (CAR)-modified T lymphocytes. CARs are engineered receptors constructed from antigen recognition regions of antibodies fused to T-cell signaling and costimulatory domains that can be used to reprogram a patient's T cells to specifically target tumor cells. CAR T-cell therapy has demonstrated sustained complete responses for some patients with advanced leukemia, and a number of CAR therapies are being evaluated in clinical studies. CAR T-cell therapy-associated toxicities, including cytokine release syndrome, macrophage activation syndrome, and tumor lysis syndrome, have been observed and effectively managed in the clinic. In patients with significant clinical responses, sustained B-cell aplasia has also been observed and is a marker of CAR T-cell persistence that might provide long-term disease control. Education on CAR T-cell therapy efficacy and safety management is critical for clinicians and patients who are considering this novel type of treatment. In the present report, the current landscape of CAR T-cell therapy, the effective management of patients undergoing treatment, and which patients are the most suitable candidates for current trials are discussed.
Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. [2018]Over half of patients diagnosed with B-cell acute lymphoblastic leukemia (ALL) develop relapsed or refractory disease. Traditional chemotherapy salvage is inadequate, and new therapies are needed. Chimeric antigen receptor (CAR) T cell therapy is a novel, immunologic approach where T cells are genetically engineered to express a CAR conferring specificity against a target cell surface antigen, most commonly the pan-B-cell marker CD19. After infusion, CAR T cells expand and persist, allowing ongoing tumor surveillance. Several anti-CD19 CAR T cell constructs have induced high response rates in heavily pre-treated populations, although durability of response varied. Severe toxicity (cytokine release syndrome and neurotoxicity) is the primary constraint to broad implementation of CAR T cell therapy. Here, we review the experience of CAR T cell therapy for ALL and ongoing efforts to modify existing technology to improve efficacy and decrease toxicity. As an anti-CD19 CAR T cell construct may be FDA approved soon, we focus on issues relevant to practicing clinicians.
Chimeric antigen receptor modified T-cells for cancer treatment. [2020]T cells engineered with the chimeric antigen receptor (CAR) are rapidly emerging as an important immunotherapy for hematologic malignancies. The anti-cluster of differentiation (CD)19 CAR-T cell therapy has been remarkably successful against refractory/relapsed acute lymphoblastic leukemia (ALL), and a complete remission rate as high as 90% was observed, in both children and adults. Although the achievement of clinical efficacy using CAR-T cell therapy for solid tumors has encountered several obstacles that were associated with the multiple mechanisms contributing to an immunosuppressive microenvironment, investigators are exploring more optimized approaches to improve the efficiency of CAR-T in solid tumors. In addition, cytokine release syndrome (CRS) and neurotoxicity following CAR-T cell therapy can be severe or even fatal; therefore, the management of these toxicities is significant. Herein, we briefly review the structure of CAR-T and some novel CAR designs, the clinical application of CAR-T cell therapies, as well as the assessment and management of toxicities.
Approaches for generation of anti-leukemia specific T cells. [2020]As three decades ago, it was reported that adoptive T cell immunotherapy by infusion of autologous tumor infiltrating lymphocytes (TILs) mediated objective cancer regression in patients with metastatic melanoma. A new era of T cell immunotherapy arose since the improvement and clinical use of anti-CD19 chimeric antigen receptor T cells (CAR-T) for the treatment of refractory and relapsed B lymphocyte leukemia. However, several challenges and difficulties remain on the way to reach generic and effective T cell immunotherapy, including lacking a generic method for generating anti-leukemia-specific T cells from every patient. Here, we summarize the current methods of generating anti-leukemia-specific T cells, and the promising approaches in the future.
Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. [2020]Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.
Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. [2021]Despite the impressive complete remission (CR) induced by CD19 CAR-T cell therapy in B-ALL, the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia. Bispecific CAR-modified T cells targeting both CD19 and CD22 may overcome the limitation of CD19-negative relapse.
Combination Therapy for Solid Tumors: Taking a Classic CAR on New Adventures. [2021]CD19-specific CAR-T cell therapies are the gold standard of adoptive cellular immunotherapy for hematopoietic malignancies. In Science Translational Medicine, Park et al. develop an oncolytic vaccinia virus that introduces truncated CD19 expression in solid tumors, which are then eradicated by CD19-specific CAR-T cells in immunodeficient and immunocompetent mouse models.
CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity? [2021]CD19-specific chimeric antigen receptor (CAR) T cell therapies have shown remarkable early success in highly refractory and relapsing hematological malignancies. However, this potent therapy is accompanied by significant toxicity. Cytokine release syndrome and neurotoxicity are the most widely reported, but the true extent and characteristics of cardiovascular toxicity remain poorly understood. Thus far, adverse cardiovascular effects observed include sinus tachycardia and other arrhythmias, left ventricular systolic dysfunction, profound hypotension, and shock requiring inotropic support. The literature regarding cardiovascular toxicities remains sparse; prospective studies are needed to define the cardiac safety of CAR T cell therapies to optimally harness their potential. This review summarizes the current understanding of the potential cardiovascular toxicities of CD19-specific CAR T cell therapies, outlines a proposed cardiac surveillance protocol for patients receiving this new treatment, and provides a roadmap of the future direction of cardio-oncology research in this area.
Development of a cGMP-compliant process to manufacture donor-derived, CD45RA-depleted memory CD19-CAR T cells. [2023]Autologous chimeric antigen receptor (CAR) T cells targeting the CD19 antigen have demonstrated a high complete response rate in relapsed/refractory B-cell malignancies. However, autologous CAR T cell therapy is not an option for all patients. Here we optimized conditions for clinical-grade manufacturing of allogeneic CD19-CAR T cells using CD45RA-depleted donor memory T cells (Tm) for a planned clinical trial. Tm were activated using the MACS GMP T Cell TransAct reagent and transduced in the presence of LentiBOOST with a clinical-grade lentiviral vector that encodes a 2nd generation CD19-CAR with a 41BB.zeta endodomain. Transduced T cells were transferred to a G-Rex cell culture device for expansion and harvested on day 7 or 8 for cryopreservation. The resulting CD19-CAR(Mem) T cells expanded on average 34.2-fold, and mean CAR expression was 45.5%. The majority of T cells were CD4+ and had a central memory or effector memory phenotype, and retained viral specificity. CD19-CAR(Mem) T cells recognized and killed CD19-positive target cells in vitro and had potent antitumor activity in an ALL xenograft model. Thus we have successfully developed a current good manufacturing practice-compliant process to manufacture donor-derived CD19-CAR(Mem) T cells. Our manufacturing process could be readily adapted for CAR(Mem) T cells targeting other antigens.
Preventing relapse after CD19 CAR T-cell therapy for pediatric ALL: the role of transplant and enhanced CAR T cells. [2023]CD19-specific chimeric antigen receptor (CAR) T-cell therapy has become an integral part of our treatment armamentarium for pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite initial remission rates of greater than 80%, durable remission occurs in only 40% to 50% of patients. In this review we summarize our current knowledge of the role of consolidative hematopoietic cell transplantation in the management of pediatric patients who achieved a minimal residual disease-negative complete response post CD19 CAR T-cell therapy. In addition, we review approaches to enhance effector function CD19 CAR T cells, focusing on how to improve persistence and prevent the emergence of CD19- B-ALL blasts.