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: CNS pathology, Autoimmune disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This phase Ib trial tests the safety, side effects, and effectiveness of humanized (hu)CD19-chimeric antigen receptor (CAR) T cell therapy in treating patients with CD19 positive B-cell acute lymphoblastic leukemia (ALL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CAR T-cell therapy is a 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, such as CD19, 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 huCD19 positive CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Chemotherapy drugs, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. huCD19-CAR T cell therapy may be safe, tolerable and effective in treating patients with relapsed or refractory CD19 positive ALL.
Will I have to stop taking my current medications?
The trial requires that certain medications be stopped before participation. For example, systemic chemotherapy must be stopped at least 2 weeks before a key procedure, and there are specific timeframes for stopping steroids, vincristine, and other drugs. It's best to discuss your current medications with the study team to understand any necessary changes.
What data supports the effectiveness of the treatment CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes for Acute Lymphoblastic Leukemia?
Research shows that CD19-specific CAR T cells, similar to the treatment in question, have high initial response rates and can lead to long-term remissions in some patients with relapsed B-cell acute lymphoblastic leukemia. Additionally, CAR T-cell therapy has been shown to improve long-term survival when followed by stem cell transplantation in patients with difficult-to-treat leukemia.
12345Is CAR T Cell Therapy for Acute Lymphoblastic Leukemia generally safe in humans?
CAR T Cell Therapy for Acute Lymphoblastic Leukemia has shown antileukemic activity with manageable safety concerns. Some patients experienced mild to moderate cytokine release syndrome (CRS), but severe toxicities were not observed, and side effects were generally manageable with supportive care.
34678How is the CAR T Cell Therapy for Acute Lymphoblastic Leukemia different from other treatments?
This CAR T cell therapy is unique because it uses genetically engineered T cells to specifically target and attack leukemia cells by recognizing a marker called CD19 on their surface. Unlike traditional chemotherapy, this approach allows the modified T cells to expand and persist in the body, providing ongoing surveillance against the cancer. However, it can cause severe side effects like cytokine release syndrome and neurotoxicity, which are challenges for its broader use.
1491011Eligibility Criteria
This trial is for patients with CD19 positive B-cell acute lymphoblastic leukemia that has relapsed or is refractory. Participants must have adequate organ function and no active infections. They cannot join if they've had certain recent treatments, other cancers, central nervous system involvement by leukemia, or are pregnant.Inclusion Criteria
Left ventricular ejection fraction (LVEF) ≥ 45%
I don't have a fever above 38.5°C and no recent infections.
Prohibited medications have not been administered
+48 more
Exclusion Criteria
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent(s)
I received CAR T therapy less than 3 months ago.
I understand the study's basics and the risks/benefits of participating.
+12 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Leukapheresis and Lymphodepletion Chemotherapy
Patients undergo leukapheresis and receive lymphodepletion chemotherapy with fludarabine and cyclophosphamide
1 week
3 visits (in-person)
CAR T Cell Infusion
Patients receive huCD19-CAR T cells infusion
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
1 year monthly, then yearly up to 15 years
Participant Groups
The trial tests huCD19-CAR T cell therapy where a patient's immune cells are modified to attack cancer cells, combined with chemotherapy drugs fludarabine and cyclophosphamide. It aims to see if this approach is safe and effective against relapsed/refractory ALL.
1Treatment groups
Experimental Treatment
Group I: Treatment (huCD19-CAR T)Experimental Treatment14 Interventions
Patients undergo leukapheresis then receive lymphodepletion chemotherapy with fludarabine IV and cyclophosphamide IV on days -5, -4 and -3 and huCD19-CAR T IV cells over 10-15 minutes on day 0. Patients may optionally receive cetuximab IV over 60-120 minutes at least 28 days post T cell infusion and undergo alloHCT. Additionally, patients undergo ECHO or MUGA, CT or PET/CT and optional MRI on study and bone marrow biopsy and aspiration and blood sample collection throughout the study.
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.
Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. [2023]CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients.
Efficacy and safety of CD19 CAR-T cell therapy for patients with B cell acute lymphoblastic leukemia involving extramedullary relapse. [2022]To evaluate the efficacy and safety of CD19 chimeric antigen receptor (CAR) T cell therapy for patients with B cell acute lymphoblastic leukemia (B-ALL) involving extramedullary relapse.
[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review]. [2020]To evaluate the safety and efficacy of chimeric antigen receptors T cells (CAR-T) in childhood acute B lymphoblastic leukemia (B-ALL).
Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy. [2022]Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy followed by haploidentical hematopoietic stem cell transplantation (haplo-HSCT) markedly improves the long-term survival of patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL).
Sleeping Beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. [2021]BACKGROUNDChimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability.METHODSWe report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells.RESULTSThe cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD-). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion.CONCLUSIONSB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.TRIAL REGISTRATIONClinicalTrials.gov NCT03389035.FUNDINGThis study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).
Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL. [2023]A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).
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.
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.
CAR-T Cell Therapy for Acute Lymphoblastic Leukemia: Transforming the Treatment of Relapsed and Refractory Disease. [2019]Genetically engineered T cells expressing a chimeric antigen receptor (CAR-T) targeting specific antigens present on acute lymphoblastic leukemia (ALL) blasts have generated promising results in children and adults with relapsed and refractory disease. We review the current evidence for CAR-T cell therapy in ALL, associated toxicities, and efforts to improve durable response to therapy.
Improving CAR T-cells: The next generation. [2021]The introduction of chimeric antigen receptor (CAR) T-cell therapy in acute lymphoblastic leukemia (ALL) has dramatically altered the landscape of treatment options available to children and adults with ALL. With complete remission induction rates exceeding 70% in most trials and FDA approval of one CD19 CAR T-cell construct in ALL, CAR T-cell therapy has become a mainstay in the ALL treatment algorithm for those with relapsed/refractory disease. Despite the high remission induction rate, with growing experience using CAR T-cell therapy in ALL, a host of barriers to maintaining long-term durable remissions have been identified. Specifically, relapse after, resistance to, or loss of long-term CAR T-cell persistence may all hinder CAR T-cell efficacy. In this review, we provide an overview of the current limitations which inform the design of the next generation of CAR T-cells and discuss advances in CAR T-cell engineering aimed to improve upon outcomes with CAR T-cell-based therapy in ALL.