CART22 Therapy for B-Cell Leukemia

Overseen By Brooke Leibfreid

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Hepatitis B, Hepatitis C, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 1 week

41 Participants Needed

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. ^{1 2 3 4 5}

What 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. ^{6 7 8 9 10}

How 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. ^{1 2 4 11 12}

Research Team

Stephan Grupp, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility 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.

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)

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

Treatment Details

Interventions

• CART22 cells

Trial Overview 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.

Participant Groups

Group I: Pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia Experimental Treatment 3 Interventions

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Findings from Research

In a study of 42 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), those treated with anti-CD19 CAR T cells showed a complete response (CR) rate of 28% and an overall response rate of 44% after 4 weeks, with a median overall survival of 64 months.

Achieving a complete response was linked to significantly longer overall survival and progression-free survival, indicating that the effectiveness of CAR T cell therapy is enhanced in patients who reach CR, regardless of whether they received a low or high dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. Frey, NV., Gill, S., Hexner, EO., et al.[2021]

Chimeric antigen receptor T-cell (CART) therapy targeting CD22 is effective in inducing remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL), but many remissions are short-lived due to reduced CD22 expression on leukemic cells.

Using Bryostatin1 to upregulate CD22 expression significantly enhances CART functionality and persistence, leading to longer-lasting responses in vivo, despite some reduction in IFNγ production by CART.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence. Ramakrishna, S., Highfill, SL., Walsh, Z., et al.[2021]

CART19 therapy, which targets CD19, has shown significant success in treating relapsed/refractory B cell acute lymphoblastic leukemia (ALL) in patients aged 25 and younger, making it a standard treatment for this age group.

For older adults, CART19 therapy is more complex and typically only available through clinical trials, requiring careful evaluation of treatment goals, potential for stem cell transplants, and the specific risks and benefits of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T in adult ALL: When and for whom? Connor, MP., Frey, NV.[2022]

In a study of 33 diffuse large B cell lymphoma (DLBCL) patients, low levels of differentiated CD3+CD27-CD28- T cells before CART cell therapy were found to be a strong predictor of overall response and complete remission, suggesting their potential as a biomarker for treatment efficacy.

Despite having similar cytotoxic capabilities, CD3+CD8+ T cells were more effective than CD3+CD4+ T cells in killing CD19+ target cells, highlighting the importance of T cell type in the effectiveness of CART cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The frequency of differentiated CD3+CD27-CD28- T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. Worel, N., Grabmeier-Pfistershammer, K., Kratzer, B., et al.[2023]

Chimeric antigen receptor T (CART) cell therapy is effective against relapsed/refractory B-cell hematological cancers but has a high relapse rate due to factors like T-cell exhaustion and the presence of inhibitory receptors.

The mechanisms behind CD19+ relapse include genetic changes in B cells and the presence of CD19 subclones, but these challenges may be addressed with new pharmacological interventions and improved CAR designs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of failure of chimeric antigen receptor T-cell therapy. Li, X., Chen, W.[2020]

CAR-modified T-cell therapy targeting CD19 has shown impressive remission rates of 50% to 60% at 1 year for patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), marking a significant advancement in treatment for this challenging condition.

While the therapy is effective, it can lead to side effects such as cytokine release syndrome (CRS) and neurotoxicity shortly after treatment, as well as long-term B-cell aplasia, which are important considerations for patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL. DiNofia, AM., Maude, SL.[2020]

Chimeric antigen receptor T-cell (CART) therapy has achieved impressive complete remission rates of 65% to 90% in pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), marking a significant advancement in treatment.

The introduction of CART therapy has also brought new toxicity profiles and treatment challenges, highlighting the need for standardized toxicity grading systems and innovative management strategies to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-cell Therapy: Current Status and Clinical Outcomes in Pediatric Hematologic Malignancies. Talleur, AC., Myers, R., Annesley, C., et al.[2022]

In a study involving five pediatric patients who relapsed after CD19-targeted CAR-T therapy, co-administration of CD19- and CD22-targeted CAR-T cells resulted in 100% of patients achieving minimal residual disease-negative complete remission, demonstrating high efficacy as a salvage therapy.

The treatment was found to be safe, with only mild cytokine release syndrome observed and no neurological toxicity, allowing for successful bridging to allogeneic hematopoietic stem cell transplantation in three patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of co-administration of CD19 and CD22 CAR-T cells in children with B-ALL relapse after CD19 CAR-T therapy. Li, W., Ding, L., Shi, W., et al.[2023]

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has become a significant advancement in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), with two such therapies approved by regulatory agencies.

Despite the success of CD19-targeting CAR T-cells, some patients still experience relapses, highlighting the need for ongoing research into resistance mechanisms and potential strategies to overcome them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. Saleh, K., Pasquier, F., Bigenwald, C., et al.[2023]

Anti-CD19 CAR T-cell therapy has shown high response rates in treating relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), but many patients experience relapse due to the therapy's limited persistence and tumor escape mechanisms.

The review highlights new CAR targets and strategies to enhance CAR T-cell effectiveness while also addressing serious side effects like cytokine release syndrome and neurotoxicity, aiming to improve patient outcomes in R/R B-ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19. Acharya, L., Garg, A., Rai, M., et al.[2023]

CD22 is a key surface molecule found on most B-cell acute lymphoblastic leukemia (B-ALL) cells, and therapies targeting CD22, like inotuzumab, have shown promising results, with up to 80% of treated patients achieving complete remission.

Current treatments for B-ALL have high relapse rates, but novel immune-targeted therapies may improve outcomes by effectively targeting chemo-refractory cells, suggesting that analyzing CD22 expression could help predict treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults. Lanza, F., Maffini, E., Rondoni, M., et al.[2023]

The novel CD19-specific CAR T cells incorporating CD28 and IL-15Rα (153z CAR) showed superior T cell expansion and prolonged cytotoxic activity against target cells, indicating enhanced therapeutic potential.

A clinical case demonstrated that a patient with acute lymphoblastic leukemia, who had multiple relapses and failed conventional treatments, achieved complete remission after receiving the 153z CAR T cell therapy, suggesting promising efficacy in treating resistant cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Rα Signaling. Nair, S., Wang, JB., Tsao, ST., et al.[2020]

References

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

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. [2021]

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

Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence. [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

CAR T in adult ALL: When and for whom? [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The frequency of differentiated CD3+CD27-CD28- T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. [2023]

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

Mechanisms of failure of chimeric antigen receptor T-cell therapy. [2020]

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

Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL. [2020]

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

Chimeric Antigen Receptor T-cell Therapy: Current Status and Clinical Outcomes in Pediatric Hematologic Malignancies. [2022]

8. England pubmed.ncbi.nlm.nih.gov

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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. [2023]

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

Novel chimeric antigen receptor targets and constructs for acute lymphoblastic leukemia: Moving beyond CD19. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults. [2023]

12. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Rα Signaling. [2020]