CAR T Cell Therapy for Acute Lymphoblastic Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: City of Hope Medical Center
Must not be taking: Systemic steroids, Immunosuppressants
Disqualifiers: Autoimmune disease, Cardiovascular disability, others
No Placebo Group
Approved in 6 Jurisdictions
Trial Summary
What is the purpose of this trial?This phase I trial tests the safety, side effects, and best dose of autologous anti-CD19 CAR-expressing T lymphocytes (CD19-CAR T cells) in older adults with B-cell acute lymphoblastic leukemia. Chimeric antigen receptor (CAR) T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of B-cell acute lymphoblastic leukemia.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it does exclude those using systemic steroids or chronic immunosuppressants. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment Autologous Anti-CD19 CAR-expressing T Lymphocytes for Acute Lymphoblastic Leukemia?
Research shows that CD19 CAR T-cell therapy can lead to high remission rates in patients with relapsed or refractory acute lymphoblastic leukemia, with one study reporting a 90% remission rate. However, long-term remission is achieved in about 40% to 50% of patients, indicating the treatment's potential but also highlighting the need for further strategies to maintain remission.
12345Is CAR T Cell Therapy for Acute Lymphoblastic Leukemia safe for humans?
CAR T Cell Therapy, specifically targeting CD19, has been generally well tolerated in clinical trials for acute lymphoblastic leukemia, with manageable side effects like cytokine release syndrome (a condition where the immune system is overly activated) and neurotoxicity (nervous system side effects). Most side effects have been temporary or manageable with supportive care, and the therapy has shown a favorable safety profile in both children and adults.
46789How is the treatment Autologous Anti-CD19 CAR-expressing T Lymphocytes unique for acute lymphoblastic leukemia?
This treatment uses a patient's own T-cells, which are modified to target and kill leukemia cells by recognizing a specific protein called CD19 on their surface. It offers a personalized approach and has shown high initial remission rates, although maintaining long-term remission can be challenging.
134510Eligibility Criteria
Adults aged 55 or older with B-cell acute lymphoblastic leukemia in first remission can join this trial. They must have a good performance status, proper liver and kidney function, and no severe infections like HIV or hepatitis. Women of childbearing age need a negative pregnancy test and agree to use birth control.Inclusion Criteria
Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease)
My cancer is in its first full remission.
Agreement to allow the use of archival tissue from diagnostic tumor biopsies. Exceptions may be granted with Study Principal Investigator (PI) approval
+17 more
Exclusion Criteria
I tested negative for active hepatitis B.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent(s)
My brain or spinal cord cancer hasn't responded to specific treatments but is now in remission.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Leukapheresis and Pre-treatment
Patients undergo T cell leukapheresis and receive fludarabine and cyclophosphamide intravenously
1-2 weeks
Multiple visits for leukapheresis and chemotherapy administration
Treatment
Patients receive CD19-CAR T cell infusion intravenously
1 day
1 visit (in-person) for infusion
Follow-up
Participants are monitored for safety, effectiveness, and adverse events after treatment
28 days
Regular visits for monitoring adverse events and response
Long-term Follow-up
Participants are monitored for event-free survival, overall survival, and relapse
Up to 15 years
Participant Groups
The trial is testing the safety and optimal dose of modified T cells (CD19-CAR T cells) that are designed to target leukemia cells in older adults. It involves taking the patient's own immune cells, modifying them in a lab, growing large numbers, and infusing them back into the patient.
1Treatment groups
Experimental Treatment
Group I: Treatment (CD19-CAR T cells)Experimental Treatment7 Interventions
Patients undergo T cell leukapheresis, receive fludarabine and cyclophosphamide IV, and then receive CD19-CAR T cell infusion IV on study.
Autologous Anti-CD19 CAR-expressing T Lymphocytes is already approved in United States, European Union, United States, European Union, United States, European Union for the following indications:
🇺🇸 Approved in United States as Tisagenlecleucel (Kymriah) for:
- B-cell acute lymphoblastic leukemia (ALL)
- Large B-cell lymphoma (LBCL)
🇪🇺 Approved in European Union as Tisagenlecleucel (Kymriah) for:
- B-cell acute lymphoblastic leukemia (ALL)
- Diffuse large B-cell lymphoma (DLBCL)
🇺🇸 Approved in United States as Axicabtagene ciloleucel (Yescarta) for:
- Large B-cell lymphoma (LBCL)
- Follicular lymphoma (FL)
🇪🇺 Approved in European Union as Axicabtagene ciloleucel (Yescarta) for:
- Diffuse large B-cell lymphoma (DLBCL)
- Follicular lymphoma (FL)
🇺🇸 Approved in United States as Lisocabtagene maraleucel (Breyanzi) for:
- Large B-cell lymphoma (LBCL)
- Follicular lymphoma (FL)
🇪🇺 Approved in European Union as Lisocabtagene maraleucel (Breyanzi) for:
- Diffuse large B-cell lymphoma (DLBCL)
- Follicular lymphoma (FL)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope Medical CenterDuarte, CA
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Who Is Running the Clinical Trial?
City of Hope Medical CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. [2022]Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(-) disease. We report that CD19(-) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(-) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(-) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.
Low Level Donor Chimerism of CD19 CAR-T Cells Returned to Complete Donor Chimerism in Patients with Relapse After Allo-Hematopoietic Stem Cell Transplant. [2022]To investigate the donor chimerism changes and curative effects associated with the use of autologous anti-CD19 chimeric antigen receptor (CAR) T cells with B-cell acute lymphoblastic leukemia (B-ALL) presenting with a low donor chimerism level and relapse after allogeneic hematopoietic stem cell transplant (allo-HSCT).
Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. [2018]Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined.
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.
Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. [2019]Autologous CD19 chimeric-antigen receptor (CAR) T cells demonstrated remarkable remission rates in relapsed and refractory acute lymphoblastic leukemia (R/R ALL). Here, we report results from a phase 1b/2 study of in-house produced CD19 CAR with a CD28 costimulatory domain. Twenty-one patients with R/R ALL were enrolled, and 20 infused. The median age was 11 years (range, 5-48). Patients had a median of 4 prior regimens, including blinatumomab in 6 and prior stem-cell transplantation in 10. In total 8 patients had extramedullary (EM) leukemic involvement, and prior to lymphodepletion and CAR 7 had active lesions, a group underrepresented in previous trials. In vivo expansion of CAR T cells was observed in 18 patients. In total 16 patients developed cytokine release syndrome, and 11 patients developed neurotoxicity, with no toxic deaths. All responding patients were referred to an allogeneic hematopoietic stem-cell transplantation. The remission rate was 90%, including resolution of all refractory EM sites. Four responding patients relapsed, 3 who had a PCR-MRD positive remission at 28 days following CAR-T cells and 1 patient 21 months after an MRD-negative response. The estimated 1-year event-free survival and overall survival are 73% and 90%, respectively. Patients with R/R EM ALL may also benefit from CAR-T cell therapy.
CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). [2020]Relapsed and chemotherapy-refractory B-cell acute lymphoblastic leukemia (B-ALL) remain significant causes of cancer-associated morbidity and mortality for children and adults. Development of new molecularly targeted treatment strategies for patients with high-risk B-ALL is thus a major preclinical and clinical priority. Adoptive cellular therapy with patient-derived human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CD19 CAR T cells) is one immunotherapeutic modality that has recently demonstrated remarkable efficacy in re-inducing remission in patients with multiply relapsed B-ALL. Investigative teams at several major cancer centers are currently conducting phase I clinical trials in children and/or adults with relapsed/refractory B-ALL to assess the safety and to identify the maximally tolerated dose of each group's CD19 CAR T-cell product. All groups have reported major clinical toxicities associated with CD19 CAR T-cell treatment, including cytokine release syndrome (CRS) and macrophage activation syndrome, neurologic dysfunction and aplasia of normal B lymphocytes, while CD19 CAR T cells persist in vivo. Toxicities have generally been transient or manageable with supportive care measures. Some patients with life-threatening CD19 CAR T-cell induced sequelae have received anti-cytokine receptor antibody treatment to diminish CRS symptoms and/or corticosteroids to terminate CAR T-cell proliferation. Remarkably, 67-90% of children and adults with B-ALL treated with CD19 CAR T cells in these trials have achieved morphologic leukemia remission with many patients also in molecular remission. The duration of CD19 CAR T cell persistence in vivo has varied appreciably among treated patients and likely reflects differences in the CD19 CAR constructs utilized at each institution. CD19-positive and CD19-negative B-ALL relapses after CD19 CAR T-cell treatment have occurred in some patients. Phase II trials to assess the efficacy of CD19 CAR T-cell immunotherapy in larger cohorts of patients with relapsed/refractory B-ALL are ongoing or planned.
Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. [2023]Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 (NCT02935257) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL.
CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. [2022]Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.
Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. [2022]T cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n = 12). Treatment was well tolerated, with a low incidence of both cytokine release syndrome (any grade, n = 6) and neurotoxicity (any grade, n = 3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow (BM). High disease burden (≥40% morphologic blasts) before CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. After infusion, CD8+ CAR T cells had a proliferative advantage over CD4+ CAR T cells and at peak expansion, had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation (AlloHCT) had sustained, durable responses. In summary, the initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03573700.
Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. [2022]Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells.