CAR T-Cell Therapy for Leukemia and Lymphoma

Recruiting in Palo Alto (17 mi)

Overseen by Nirali N. Shah

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Waitlist Available

Sponsor: National Cancer Institute (NCI)

No Placebo Group

Trial Summary

What is the purpose of this trial?

Background: B-cell leukemias and lymphomas are cancers that are often difficult to treat. The primary objective of this study is to determine the ability to take a patient's own cells (T lymphocytes) and grow them in the laboratory with the CD19/CD22-CAR receptor gene through a process called 'lentiviral transduction (also considered gene therapy) and growing them to large numbers to use as a treatment for hematologic cancers in children and young adults.. Researchers want to see if giving modified CD19/CD22-CAR T cells to people with these cancers can attack cancer cells. In addition, the safety of giving these gene modified cells to humans will be tested at different cell doses. Additional objectives are to determine if this therapy can cause regression of B cell cancers and to measure if the gene modified cells survive in patients blood. Objective: To study the safety and effects of giving CD19/CD22-CAR T cells to children and young adults with B-cell cancer. Eligibility: People ages 3-39 with certain cancers that have not been cured by standard therapy. Their cancer tissue must express the CD19 protein. Design: A sample of participants blood or bone marrow will be sent to NIH and tested for leukemia. Participants will be screened with: Medical history Physical exam Urine and blood tests (including for HIV) Heart and eye tests Neurologic assessment and symptom checklist. Scans, bone marrow biopsy, and/or spinal tap Some participants will have lung tests. Participants will repeat these tests throughout the study and follow-up. Participants will have leukapheresis. Blood will be drawn from a plastic tube (IV) or needle in one arm then go through a machine that removes lymphocytes. The remaining blood will be returned to the participant s other arm. Participants will stay in the hospital about 2 weeks. There they will get: Two chemotherapy drugs by IV Their changed cells by IV Standard drugs for side effects Participants will have frequent follow-up visits for 1 year, then 5 visits for the next 4 years. Then they will answer questions and have blood tests every year for 15 years. ...

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had systemic chemotherapy, anti-neoplastic investigational agents, or antibody-based therapies within 2 weeks prior to apheresis, with some exceptions. It's best to discuss your specific medications with the trial team.

What data supports the idea that CAR T-Cell Therapy for Leukemia and Lymphoma is an effective treatment?

The available research shows that CAR T-Cell Therapy, specifically targeting CD19 and CD22, is effective for treating leukemia and lymphoma. One study found that using both CD19 and CD22 targets helps overcome issues that occur when only one target is used, like the cancer coming back. Another study highlighted that using fludarabine and cyclophosphamide before the CAR T-Cell Therapy improved outcomes for patients with a type of leukemia. This combination helped patients live longer without the cancer returning. Additionally, a case report showed that even when using an alternative drug, clofarabine, before the therapy, the treatment was still effective, leading to remission in a patient with leukemia. These findings suggest that CAR T-Cell Therapy is a promising treatment option for these cancers. ^{1 2 3 4 5}

What safety data is available for CAR T-Cell Therapy targeting CD19/CD22 in leukemia and lymphoma?

Safety data for CD19/CD22 CAR T-Cell Therapy indicates that severe cytokine release syndrome (CRS) and neurotoxicity are potential risks. In one study, severe CRS was observed in 13% of patients, and grade ≥3 neurotoxicity in 28%. Another study reported severe grade 4 CRS in 1 patient, with no neurotoxicity observed. A third study found no severe grade 4 CRS, with grade 3 CRS in 7 patients and mild neurotoxic effects in 3 patients. Overall, toxicities were transient and reversible, with no CAR-T-related mortality reported. The addition of fludarabine to the lymphodepletion regimen improved outcomes and minimized immune responses that could limit CAR-T cell expansion and efficacy. ^{1 3 6 7 8}

Is the treatment CD19/CD22 CAR T-Cells, Cyclophosphamide, Fludarabine a promising treatment for leukemia and lymphoma?

Yes, the CD19/CD22 CAR T-Cell treatment is promising for leukemia and lymphoma. It targets two proteins on cancer cells, which helps prevent the cancer from escaping treatment. Studies show it can be effective in patients who have not responded to other treatments. ^{1 9 10 11 12}

Research Team

Nirali N. Shah

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for children and young adults aged 3-39 with specific B-cell cancers that haven't been cured by standard treatments. Participants must have CD19 protein on their cancer cells, be in good health otherwise, able to perform daily activities, and not pregnant or breastfeeding. They should also agree to use birth control during the study.

Inclusion Criteria

My B cell ALL or lymphoma has not responded to at least two treatments.

I have no other curative treatment options and cannot undergo or have chosen not to undergo a stem cell transplant.

I am between 3 and 39 years old.

Exclusion Criteria

My condition is rapidly worsening, which may prevent me from completing the treatment.

I have had previous treatments for my condition.

I have previously undergone CAR therapy or similar treatments.

Treatment Details

Interventions

• CD19/CD22 CAR T-Cells (CAR T-cell Therapy)
• Cyclophosphamide (Alkylating agents)
• Fludarabine (Anti-metabolites)

Trial Overview The trial tests a new therapy using the patient's own T cells modified with CD19/CD22-CAR genes to fight B-cell leukemia and lymphoma. It involves taking blood or bone marrow samples, giving chemotherapy drugs Cyclophosphamide and Fludarabine, then infusing the engineered CAR T-cells back into patients.

Participant Groups

Group I: Dose expansion Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells at MTD or highest dose administered

Group II: Dose escalation Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells at escalating doses

CD19/CD22 CAR T-Cells is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as CD19/CD22 CAR T-Cell Therapy for:

• Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

🇪🇺 Approved in European Union as CD19/CD22 CAR T-Cell Therapy for:

• Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia
• Large B-Cell Lymphoma

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14080

Patients Recruited

41,180,000+

References

1. United States pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis. [2023] The efficacy of CD22 or CD19 chimeric antigen receptor T (CAR-T) cells in the management of acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) was observed. Because antigen loss and lack of CAR-T-cell persistence are the leading causes of progressive disease following single-antigen targeting, we evaluated CD22/CD19 dual-targeting CAR-T-cell therapy efficacy and safety in relapsed/refractory B-cell malignancies.

2. United States pubmed.ncbi.nlm.nih.gov

Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report. [2023] Given the shortage of fludarabine, alternative preparative lymphodepleting regimens for CAR-T-cell therapy need to be identified. We present a case of relapsed/refractory B-cell acute lymphoblastic leukemia requiring multiple lines of salvage therapy with persistent extensive disease, who underwent lymphodepletion with clofarabine and cyclophosphamide before tisagenlecleucel CD19+ CAR-T-cell infusion with eventual remission. We offer evidence of clofarabine's activity against B-cell acute lymphoblastic leukemia in combination with tisagenlecleucel therapy. In this patient, clofarabine did not decrease CAR-T-cell effectiveness, supported by presence of cytokine release syndrome and ultimate minimal residual disease negativity both on flow cytometry and next-generation sequencing.

3. United States pubmed.ncbi.nlm.nih.gov

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. [2022] The addition of fludarabine to cyclophosphamide as a lymphodepleting regimen prior to CD19 chimeric antigen receptor (CAR) T-cell therapy significantly improved outcomes in patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Fludarabine exposure, previously shown to be highly variable when dosing is based on body surface area (BSA), is a predictor for survival in allogeneic hematopoietic cell transplantation (allo-HCT). Hence, we hypothesized that an optimal exposure of fludarabine might be of clinical importance in CD19 CAR T-cell treatment. We examined the effect of cumulative fludarabine exposure during lymphodepletion, defined as concentration-time curve (AUC), on clinical outcome and lymphocyte kinetics. A retrospective analysis was conducted with data from 26 patients receiving tisagenlecleucel for r/r B-ALL. Exposure of fludarabine was shown to be a predictor for leukemia-free survival (LFS), B-cell aplasia, and CD19-positive relapse following CAR T-cell infusion. Minimal event probability was observed at a cumulative fludarabine AUCT0-∞ ≥14 mg*h/L, and underexposure was defined as an AUCT0-∞

4. England pubmed.ncbi.nlm.nih.gov

A trial of fludarabine and cyclophosphamide combination chemotherapy in the treatment of advanced refractory primary cutaneous T-cell lymphoma. [2019] The combination of fludarabine and cyclophosphamide shows synergistic toxicity in vitro and has been used to treat nodal non-Hodgkin's lymphoma and relapsed chronic lymphocytic leukaemia.

5. United States pubmed.ncbi.nlm.nih.gov

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. [2021] Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%.

6. United States pubmed.ncbi.nlm.nih.gov

Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. [2022] CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4(+)/CD8(+) ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.

7. United States pubmed.ncbi.nlm.nih.gov

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study. [2022] Chimeric antigen receptor (CAR) T-cell therapies that target either CD19 or CD22 alone have potent antilymphoma effects. However, antigen escape-mediated relapse often occurs. CAR T cells targeting both CD19 and CD22 may overcome this limitation. In this study, we developed bispecific CAR T cells simultaneously recognizing CD19- and CD22-expressing targets and assessed their safety and efficacy profiles in patients with relapsed/refractory aggressive B-cell lymphoma. Twenty-four patients were screened, and 16 were found eligible for the study. CAR T-cell-associated toxicities were recorded. Responses, overall survival (OS), and progression-free survival (PFS) were assessed. Of the 16 eligible patients, 14 (87.5%) achieved objective response and 10 (62.5%) achieved complete response (CR). The 2-year OS and PFS rates were 77.3% and 40.2%, respectively. Achieving CR (P = 0.046) and the number of prior chemotherapy lines (n = 2; P = 0.047) were independent prognostic factors associated with favorable PFS. The 2-year OS and PFS among patients who achieved CR were higher than among those who did not (P = 0.015 and P &lt; 0.001, respectively). The 2-year PFS among patients who received two prior lines of chemotherapy was higher than that among patients who received more than two lines of chemotherapy (P = 0.049); OS did not differ between the groups. Severe grade 4 cytokine-release syndrome (CRS) was observed in 1 patient; 4 and 11 patients had grades 1 and 2 CRS, respectively. No patients developed neurotoxicity. CD19/CD22 dual-targeted CAR T cells may be a safe, potent antilymphoma cell-based targeted immunotherapy.

8. Switzerland pubmed.ncbi.nlm.nih.gov

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients. [2022] Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40% patients have achieved sustained responses. Here, we conducted a phase II clinical trial testing efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin's lymphoma patients (NCT03196830). Among enrolled patients, 33 R/R DLBCL patients pretreated with DFC (decitabine, fludarabine plus cyclophosphamide) lymphodepletion chemotherapy and infused with tandem CD19-CD22 based CAR-T cells were drawn out for efficacy and toxicities of CAR-T therapy evaluation. With a median follow-up of 10.9(0.6-29.0) months, the best overall response and complete remission (CR) rates were 90.9% and 63.6%, respectively. The median progression-free survival (PFS) was 10.2 months and overall survival (OS) was undefined. The 2-year OS and PFS rates were 54.3% and 47.2%, respectively. No severe grade 4 cytokine release syndrome (CRS) was observed and grade 3 CRS was observed in only 7 patients; 3 patients developed mild immune effect or cell-associated neurotoxic syndrome. All toxicities were transient and reversible and no CAR-T-related mortality. Further subgroup analysis showed that achieving CR was an independent prognostic factor associated with favorable PFS and OS. The 2-year OS and PFS for patients who achieved CR within 3 months (undefined versus undefined P=0.021 and undefined versus undefined P=0.036) or during the follow-up period were significantly longer than those who did not (undefined versus 4.6 months P &lt; 0.0001 and undefined versus 2.0months P&lt;0.001). While severe CRS was also an independent prognostic factor but associated with inferior PFS and OS. The 2-year OS and PFS for patients with grade 3 CRS were significantly shorter than those with grade 0-2 CRS (4.1 months versus undefined P&lt;0.0001 and 1.7 months versus undefined P=0.0002). This study indicated that CD19/CD22 dual-targeted CAR-T therapy under a decitabine-containing lymphodepletion regimen may be a safe, potent effective approach to R/R DLBCL patients.

9. Netherlands pubmed.ncbi.nlm.nih.gov

T-cells fighting B-cell lymphoproliferative malignancies: the emerging field of CD19 CAR T-cell therapy. [2017] CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor (CAR). The CAR contains an antigen recognition part (originating from an antibody), a T-cell receptor transmembrane and cytoplasmic signalling part, and one or more co-stimulatory domains. While CAR T-cells can be directed against any tumour target, most experience thus far has been obtained with targeting of the B-cell antigen CD19 that is expressed by B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia and other B-cell lymphomas. The first clinical results are promising, although there are profound differences in response between patients with different haematological malignancies. Treatment-related side effects have been observed that require specific management. This review will explain the mechanism of action, summarise the experience to date and point out future directions for this hopeful new addition to the therapeutic armamentarium in the treatment of lymphoproliferative B-cell malignancies.

10. England pubmed.ncbi.nlm.nih.gov

Engineering Novel CD19/CD22 Dual-Target CAR-T Cells for Improved Anti-Tumor Activity. [2022] Despite high remission rates following chimeric antigen receptor T cell (CAR-T) cell therapy in B-cell acute lymphoblastic leukemia (B-ALL), relapse due to loss of the targeted antigen is increasingly recognized as a mechanism of immune escape. We hypothesized that simultaneous targeting of CD19 and CD22 may improve the CAR-T effect. The in&#160;vitro and in&#160;vivo leukemia model was established, and the anti-tumor effects of BiCAR-T, CD19 CAR-T, CD22 CAR-T, and LoopCAR6 cells were observed. We found that the BiCAR-T cells showed significant cytotoxicity in&#160;vitro and in&#160;vivo. The CD19/CD22 bivalent CAR provides an opportunity to test whether simultaneous targeting may reduce the risk of antigen loss.

11. England pubmed.ncbi.nlm.nih.gov

Haploidentical CD19/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation. [2020] Chimeric antigen receptor T (CAR-T) cell therapy simultaneously against CD19 and CD22 is an attractive strategy to address the antigen escape relapse after CD19-directed CAR-T cell therapies. However, the potential of optimizing the durability of remission by this approach in patients with B cell acute lymphoblastic leukemia (B-ALL) remains a critical unanswered question so far.

12. England pubmed.ncbi.nlm.nih.gov

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.