CAR T-Cell Therapy for Acute Lymphoblastic Leukemia

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 & 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antidepressants, Antineoplastics, others

Disqualifiers: CNS disease, Hyperleukocytosis, Pregnancy, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses. Objective: To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL. Eligibility: People aged 3 to 39 with ALL or related B-cell lymphoma that has not been cured by standard therapy. Design: Participants will be screened. This will include: Physical exam Blood and urine tests Tests of their lung and heart function Imaging scans Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone. Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord. Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells. Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment. Participants will be admitted to the hospital. Their own modified T cells will be returned to their body. Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years....

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but there are specific 'washout' periods (time without taking certain medications) for some treatments. For example, you need to stop systemic chemotherapy and certain other therapies at least 2 weeks before starting the trial, with longer periods for specific drugs like clofarabine. However, some medications like intrathecal chemotherapy and certain maintenance therapies may not require a washout period.

What data supports the effectiveness of the treatment CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells, CD19/CD22 CAR T Cells, AUTO3 for Acute Lymphoblastic Leukemia?

Research shows that the AUTO3 treatment, which targets both CD19 and CD22, had an 86% remission rate in patients with B-cell acute lymphoblastic leukemia one month after treatment. This dual targeting approach may help prevent relapse by addressing the loss of the targeted antigen, a common issue with single-target therapies. ^{1 2 3 4 5}

Is CAR T-Cell Therapy for Acute Lymphoblastic Leukemia safe?

In a study with pediatric and young adult patients using AUTO3 (a type of CAR T-Cell therapy targeting CD19 and CD22), the treatment showed a favorable safety profile with no severe side effects like cytokine release syndrome or neurotoxicity reported. ^{1 6 7 8 9}

What makes the CD19/CD22 CAR T-Cell treatment unique for acute lymphoblastic leukemia?

This treatment is unique because it targets two proteins, CD19 and CD22, on cancer cells, which helps prevent the cancer from escaping treatment by losing one of these proteins. This dual targeting approach aims to improve the effectiveness and reduce the chance of relapse compared to treatments that target only one protein. ^{1 2 3 5 6}

Eligibility Criteria

This trial is for children and young adults aged 3 to 35 with B-cell malignancies like ALL or lymphoma that's come back or didn't respond to treatment. They must have tried at least one standard chemo and one additional therapy, may have had a stem cell transplant, and can't be pregnant or breastfeeding. Participants need decent heart and lung function, no severe infections (HIV/HBV/HCV), no other cancers unless cured over two years ago, and must agree to birth control measures.

Inclusion Criteria

My cancer did not respond to initial chemotherapy and a follow-up treatment.

My tests show some remaining cancer cells or active cancer.

My cancer is a type of blood cancer like ALL, CML in ALL phase, or high-grade lymphoma.

Exclusion Criteria

Participants with positive serum or urine beta-HCG pregnancy test performed at screening

I have active brain lymphoma or symptoms of it.

I meet the required waiting period after my last cancer treatment before joining this trial.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for physical exam, blood and urine tests, imaging scans, bone marrow biopsy, and lumbar puncture

Apheresis

Participants undergo apheresis to collect T cells for modification

1 day

1 visit (in-person)

Chemotherapy

Participants receive chemotherapy 4 or 5 days before CAR T-cell treatment

4-5 days

Inpatient stay

Treatment

Participants receive CD19/CD22-CAR T-cell infusion

1 day

Inpatient stay

Initial Follow-up

Participants visit the clinic 2 times a week for 28 days after treatment

4 weeks

8 visits (in-person)

Long-term Follow-up

Participants are monitored for safety and effectiveness, with follow-up continuing for 15 years

15 years

Regular visits as per protocol

Treatment Details

Interventions

• CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells (CAR T-cell Therapy)

Trial Overview The study tests a new CAR T-cell therapy targeting both CD19/CD22 proteins on cancer cells. It involves modifying the patient's own T cells in the lab after chemotherapy preparation. Patients will receive their modified T cells back into their body in hospital settings followed by regular clinic visits for monitoring over an extended period of up to 15 years.

Participant Groups

Group I: 4/Phase II Dose Expansion- with high disease burden Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD regimen #2

Group II: 3/Phase II Dose Expansion- with low disease burden Experimental Treatment 3 Interventions

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

Group III: 2b/Phase 1 Dose Escalation - high disease burden Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells

Group IV: 2/Phase I Dose Escalation- with intensified LD - CLOSED Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells + standard LD

Group V: 1b/Phase 1 Dose Escalation - low disease burden Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells

Group VI: 1/Phase I Dose Escalation-with standard LD - CLOSED Experimental Treatment 3 Interventions

CD19/CD22-CAR-transduced T cells at escalating dose + standard LD

CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as CD19/CD22 CAR T Cells for:

• Recurrent or refractory CD19/CD22-expressing B cell malignancies

🇪🇺 Approved in European Union as AUTO3 for:

• Relapsed/refractory 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

References

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

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.

2. 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.

3. 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.

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

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial. [2021] Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells.

5. 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.

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

Targeting CD19-CD22 Aids Younger Patients with ALL. [2021] In a phase I trial of chimeric antigen receptor T cells targeting CD19 and CD22 in younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia, toxicity was manageable, and five of 12 patients had complete responses.

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

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.

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

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.

9. England pubmed.ncbi.nlm.nih.gov

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.