CART22 Therapy for B-Cell Leukemia
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Pennsylvania
Must not be taking: Systemic steroids, Immunosuppressants
Disqualifiers: Hepatitis B, Hepatitis C, HIV, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a pilot study to determine the feasibility and safety of a single dose of autologous T cells expressing CD22 chimeric antigen receptors expressing tandem TCR-ζ and 4-1BB signaling domains (CART22/CART22-65s cells) in pediatric and young adult subjects with relapsed or refractory 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 you cannot use systemic steroids or immunosuppressant medications while participating. Inhaled steroids or hydrocortisone for replacement therapy are allowed.
What data supports the effectiveness of the CART22 treatment for B-Cell Leukemia?
Research shows that similar treatments, like CART therapy targeting CD22, can induce remission in 70% of patients with a type of blood cancer called acute lymphoblastic leukemia (ALL), although the remissions may not last long. This suggests that CART22 might also be effective in treating B-Cell Leukemia, but the duration of its effectiveness could be a concern.
12345What safety data exists for CART22 therapy in humans?
CART22 therapy, like other CAR T-cell treatments, can cause side effects such as cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are common in CAR T-cell therapies and are being actively researched to improve safety.
678910How is CART22 therapy different from other treatments for B-cell leukemia?
CART22 therapy is unique because it uses modified T-cells to specifically target and attack CD22 proteins on leukemia cells, which is different from traditional chemotherapy that attacks all rapidly dividing cells. This targeted approach can lead to remission in patients with relapsed or refractory B-cell leukemia, although the remissions may be short-lived due to changes in CD22 expression.
1241112Eligibility Criteria
This trial is for children and young adults aged 1-29 with relapsed or refractory B-cell acute lymphoblastic leukemia. Participants must have adequate organ function, documented CD22 tumor expression, and agree to birth control if applicable. Excluded are those with HIV, active hepatitis B/C, certain CNS diseases, use of systemic steroids/immunosuppressants (with exceptions), pregnancy/nursing women, recent investigational drug use.Inclusion Criteria
My B-cell ALL has returned or didn't respond to treatment.
Signed informed consent form must be obtained prior to any study procedure
My brain disease is responding to treatment.
+6 more
Exclusion Criteria
Pregnant or nursing (lactating) women
My brain condition is worsening or increases my risk of brain side effects.
Receipt of a prior investigational study agent within 4 weeks prior to screening visit (exceptions listed)
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single dose of autologous T cells expressing CD22 chimeric antigen receptors, administered as split fractions over 2-3 days depending on cohort assignment
1 week
3 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessment of minimal residual disease (MRD) and adverse events
1 year
Regular visits (in-person and virtual)
Long-term follow-up
Participants are monitored for long-term safety and adverse events, including cytokine release syndrome (CRS)
15 years
Participant Groups
The study tests a single dose of CART22 cells in pediatric patients. These cells are modified T cells engineered to target CD22 on leukemia cells using a special receptor called 'chimeric antigen receptors' with co-stimulatory domains TCRζ/4-1BB.
1Treatment groups
Experimental Treatment
Group I: Pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemiaExperimental Treatment3 Interventions
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Hospital of PhiladelphiaPhiladelphia, PA
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Who Is Running the Clinical Trial?
University of PennsylvaniaLead Sponsor
Children's Hospital of PhiladelphiaCollaborator
References
Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. [2021]To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence. [2021]Chimeric antigen receptor T-cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape.
CAR T in adult ALL: When and for whom? [2022]Chimeric antigen receptor T cell therapy targeting CD19 (CART19) has shown remarkable results in patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (ALL). In patients 25 years of age or younger CART19 therapy is an accepted standard of care, while the treatment of older adults is less straight forward and possible only in the context of a clinical trial. Treatment of older patients with CAR T cells requires careful consideration of overall treatment goals, suitability of a consolidative hematopoietic stem cell transplant (HSCT), alternative treatment options, patient risk profile, and anticipated responses and toxicities of the specific CAR T cell products available. Here we use patient guided examples to inform approaches to care.
The frequency of differentiated CD3+CD27-CD28- T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. [2023]Chimeric antigen receptor T (CART) cell therapy targeting the B cell specific differentiation antigen CD19 has shown clinical efficacy in a subset of relapsed/refractory (r/r) diffuse large B cell lymphoma (DLBCL) patients. Despite this heterogeneous response, blood pre-infusion biomarkers predicting responsiveness to CART cell therapy are currently understudied.
Mechanisms of failure of chimeric antigen receptor T-cell therapy. [2020]Although chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate.
Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL. [2020]Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized the care of patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Results from clinical trials across multiple institutions report remarkable remission rates with CD19-directed CAR-modified T-cell therapy. These remissions are also proving to be durable in many patients with a relapse-free survival (RFS) of approximately 50% to 60% at 1 year across several trials and institutions in this population that has been historically very difficult to treat. In addition, new products are being developed to enhance upon the original CAR T-cell products, which include a humanized CAR, allogeneic CARs, and both CD22 and biallelic CD19 and CD22 constructs. Toxicity after CAR-modified T-cell therapy is characterized by cytokine release syndrome (CRS) and neurotoxicity in the acute post-infusion period and B-cell aplasia as a long-term consequence of treatment. This review will summarize the published data thus far on the use of CAR-modified T-cell therapy in pediatric B-ALL and outline the various CAR products now being developed for this population. Delivery of this therapy and the decision to pursue hematopoietic stem cell transplant (HSCT) after treatment will be discussed.
Chimeric Antigen Receptor T-cell Therapy: Current Status and Clinical Outcomes in Pediatric Hematologic Malignancies. [2022]Chimeric antigen receptor T-cell (CART) therapy has transformed the treatment paradigm for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), with complete remission rates in key pivotal CD19-CART trials ranging from 65% to 90%. Alongside this new therapy, new toxicity profiles and treatment limitations have emerged, necessitating toxicity consensus grading systems, cooperative group trials, and novel management approaches. This review highlights the results of key clinical trials of CART for pediatric hematologic malignancies, discusses the most common toxicities seen to date, and elucidates challenges, opportunities, and areas of active research to optimize this therapy.
Safety and efficacy of co-administration of CD19 and CD22 CAR-T cells in children with B-ALL relapse after CD19 CAR-T therapy. [2023]CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in treating relapsed or refractory pediatric B-lineage acute lymphoblastic leukemia (B-ALL). However, poor results are obtained when the same product is reused in patients who relapse after CAR-T. Therefore, there is a need to explore the safety and efficacy of co-administration of CD19- and CD22-targeted CAR-T as a salvage second CAR-T therapy (CART2) in B-ALL patients who relapse after their first CD19 CAR-T treatment (CART1).
CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. [2023]B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of acute leukemia in the pediatric population. The prognosis and treatment of B-ALL have dramatically improved over the past decade with the adoption of intensive and prolonged combination chemotherapy regimens. The advent of novel immunologic agents such as blinatumomab and inotuzumab has changed the treatment landscape of B-ALL. However, patients have continued to relapse, raising the need for novel therapies. Chimeric antigen receptor (CAR) T-cells have achieved a milestone in the treatment of B-ALL. Two CD19-targeting CAR T-cells were approved by the Food and Drug Administration and the European Medicines Agency for the treatment of relapsed and/or refractory B-ALL. In this review, we review the available data regarding CD19-targeting CAR T-cells with their safety profile as well as the mechanism of resistance to these agents and the way to overcome this resistance.
Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19. [2023]Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults with a poor prognosis with relapsed or refractory (R/R) B-cell lineage ALL (B-ALL). Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown excellent response rates in RR B-ALL, but most patients relapse due to poor persistence of CAR T-cell therapy or other tumor-associated escape mechanisms. In addition, anti-CD19 CAR T-cell therapy causes several serious side effects such as cytokine release syndrome and neurotoxicity. In this review, we will discuss novel CAR targets, CAR constructs, and various strategies to boost CARs for the treatment of RR B-ALL. In addition, we discuss a few novel strategies developed to reduce the side effects of CAR.
CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults. [2023]CD22 is a surface molecule expressed early during the ontogeny of B cells in the bone marrow and spleen, and can be found on B cells isolated from the different lymphoid compartments in humans. CD22 is expressed by most blasts from the majority (60-90%) of B-cell acute lymphoblastic leukemia (B-ALL). Current therapies in adults with newly diagnosed B-ALL are associated with complete remission (CR) rates of 50-90%. However, 30-60% of these patients relapse, and only 25-40% achieve disease-free survival of three years or more. Chemotherapy regimens for patients with refractory/relapsed B-ALL are associated with CR rates ranging from 31% to 44%. Novel immune-targeted therapies, such as blinatumomab and inotuzumab (a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin), provide potential means of circumventing chemo-refractory B-ALL cells through novel mechanisms of action. Eighty percent of inotuzumab-treated B-ALL patients may achieve a CR state. This review is focused on the biological and clinical activities of CD22 antibodies in B-ALL, and provides evidence about the potential role played by qualitative and quantitative analysis of the CD22 molecule on individual B-ALL blasts in predicting the depletion of leukemic cells, and, ultimately, leading to better clinical response rates.
Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Rα Signaling. [2020]Recent studies on CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved costimulatory signals in the CAR design.