CAR T-Cell Therapy for Leukemia and Lymphoma

Recruiting at 4 trial locations

Overseen By Huda S. Salman

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Huda Salman, MD

Must not be taking: Systemic glucocorticoids, Gene therapy

Disqualifiers: Pregnancy, Active infections, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 6 weeks

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is designed as a single arm open label Phase I, 3x3, multicenter study of CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed or refractory T-cell leukemia and lymphoma. Specifically, the study will evaluate the safety and feasibility of CD4CAR T-cells. Funding Source - FDA OOPD

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

The trial does not specify if you need to stop all current medications, but you cannot use systemic glucocorticoids above replacement doses unless part of standard care. If you are on corticosteroids, you must be off all but adrenal replacement doses 3 days before the CD4CAR infusion.

Is CAR T-cell therapy safe for humans?

CAR T-cell therapy, used for treating certain types of leukemia and lymphoma, can have serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Patients are usually monitored in the hospital for at least a week to manage these risks. ^{1 2 3 4 5}

What makes CD4CAR T-cell therapy unique for treating leukemia and lymphoma?

CD4CAR T-cell therapy is unique because it uses specially engineered T cells to target and destroy CD4-expressing cancer cells, offering a new approach for aggressive lymphomas that lack effective standard treatments. This therapy is a form of gene and cellular therapy that can potentially provide lasting remissions by redirecting the immune system to attack cancer cells. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment CD4CAR T cells for leukemia and lymphoma?

Research shows that CD4CAR T cells can effectively target and eliminate CD4+ cancer cells in laboratory settings and animal models, leading to reduced tumor growth and prolonged survival in mice with T-cell lymphoma. This suggests potential effectiveness for treating similar human cancers. ^{6 7 11 12 13}

Research Team

Huda Salman, MD

Principal Investigator

Indiana University

Eligibility Criteria

Adults over 18 with certain types of T-cell leukemia or lymphoma that have come back or didn't respond to treatment can join. They must be willing to follow the study plan and have a good level of organ function, including kidney, liver, heart, and lungs. Pregnant women, those with active hepatitis B/C or HIV, low lymphocyte counts, or on high-dose steroids are excluded.

Inclusion Criteria

T-cell ≥ 500

ALT/AST < 3 x ULN

Adequate echocardiogram with EF of ≥50%

Exclusion Criteria

I do not consent to receive the treatment.

Any uncontrolled active medical disorder that would preclude participation as outlined in the opinion of the treating investigator and/or study chair

I am not using high doses of steroids, except for inhalers.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Apheresis and Manufacturing

Participants undergo apheresis to collect T-cells, which are then engineered to create CD4CAR T-cells

3-4 weeks

1 visit (in-person) for apheresis

Conditioning Chemotherapy

Participants receive conditioning chemotherapy to prepare for CD4CAR T-cell infusion

1 week

Treatment

Participants receive CD4CAR T-cell infusion and are monitored for cytokine levels and CD4CAR presence

6 weeks

Multiple visits for monitoring on days 0, 1, 3, 5, 7, 14, 28, and 42

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes

18-24 months

Quarterly clinical evaluations for 2 years, followed by biannual follow-up for 13 years

Treatment Details

Interventions

• CD4CAR

Trial Overview The trial is testing CD4CAR T-cells in patients with relapsed/refractory T-cell leukemia/lymphoma. It's an early-phase study (Phase I) looking at how safe it is and if it's feasible to use these engineered cells as treatment. Participants will receive one type of intervention without comparison.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Redirected autologous T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells)

CD4CAR is already approved in United States for the following indications:

Approved in United States as CD4CAR for:

• Relapsed or refractory T-cell leukemia and lymphoma

Who Is Running the Clinical Trial?

Huda Salman, MD

Lead Sponsor

Trials

1

Recruited

20+

Huda Salman

Lead Sponsor

Trials

3

Recruited

80+

iCell Gene Therapeutics

Industry Sponsor

Trials

15

Recruited

270+

Findings from Research

CD4-specific chimeric antigen receptor (CAR) engineered T cells (CD4CART) demonstrated strong cytotoxic effects against CD4+ T cell lymphoma in both laboratory tests and in live mice, indicating their potential as an effective treatment.

The transfer of CD4CART cells significantly reduced tumor growth and improved survival rates in mice with T cell lymphoma compared to control treatments, suggesting a promising therapeutic approach for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD4-Targeted T Cells Rapidly Induce Remissions in Mice with T Cell Lymphoma. Cheng, J., Chen, G., Lv, H., et al.[2022]

The study developed a CAR (CD4CAR) that enables CD8+ T cells to target and eliminate CD4+ T-cell lymphomas, showing effectiveness in both laboratory and patient-derived samples.

In mouse models of aggressive T-cell lymphoma, CD4CAR T cells not only suppressed tumor growth but also significantly extended survival, suggesting their potential as a new treatment option for patients with peripheral T-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Pinz, K., Liu, H., Golightly, M., et al.[2018]

In a Phase I trial involving 43 pediatric and young adult patients with leukemia, initial treatment failures were linked to poor CAR T cell expansion and rapid loss of functional CAR T cells after infusion.

For patients who achieved remission, the durability of that remission was associated with higher levels of TNF-α-secreting CAR CD8+ T cells and sufficient CD19 antigen levels at the time of treatment, suggesting these factors could help predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19 CAR T cell product and disease attributes predict leukemia remission durability. Finney, OC., Brakke, HM., Rawlings-Rhea, S., et al.[2022]

CAR T-cell therapy has shown durable remission in B-cell leukemia and lymphoma, highlighting its potential effectiveness for treating other types of cancers.

Recent advancements in CAR design and clinical application strategies aim to enhance T-cell proliferation and efficacy while minimizing toxicity, making this therapy more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity. Maus, MV., Powell, DJ.[2018]

A new simplified method for producing anti-CD19 CAR T cells was developed, which involves using anti-CD3/anti-CD28 beads and culture bags, leading to a high enrichment of T cells (98% CD3+ cells) and a significant expansion (10.6-fold).

The method demonstrated a transduction efficiency of 68% in T cells from patients with B-cell chronic lymphoblastic leukemia, indicating its potential effectiveness for adoptive immunotherapy in treating B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simplified process for the production of anti-CD19-CAR-engineered T cells. Tumaini, B., Lee, DW., Lin, T., et al.[2022]

CAR T-cell therapy is an effective treatment for acute lymphocytic leukemia and B-cell lymphoma, but it requires at least 7 days of hospitalization to monitor for serious side effects like cytokine release syndrome and neurotoxicity.

Early identification and treatment of these toxicities by nursing staff can reverse potentially life-threatening complications, highlighting the importance of objective assessment and consensus grading in managing CAR T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Emergencies: Inpatient Administration, Assessment, and Management. Jackson, S., Wheatley, T.[2021]

CAR-T cell therapy has shown remarkable efficacy in treating B cell malignancies, including leukemia, lymphoma, and multiple myeloma, with high response rates, but it comes with significant safety concerns.

The most serious side effects of CAR-T therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which require supportive care and specific treatments like tocilizumab and steroids to manage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy: the Efficacy and Toxicity Balance. Chohan, KL., Siegler, EL., Kenderian, SS.[2023]

CAR-T cell therapies, while effective for treating relapsed or refractory blood cancers, can lead to serious adverse effects such as cytokine release syndrome (CRS) and neurotoxicity, which complicate patient management.

The review discusses the pathophysiology and management strategies for these adverse events, and highlights ongoing research aimed at modifying CAR-T cells to reduce toxicity and improve patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies. Yang, C., Nguyen, J., Yen, Y.[2023]

CAR-T cell therapy has shown great promise in treating hematological cancers, with two Anti-CD19 CAR-T therapies already approved for CD19-positive leukemia and lymphoma.

However, the therapy can cause serious side effects like cytokine release syndrome and on-target off-tumor toxicity, leading to some patients discontinuing treatment; researchers are exploring various safety strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Yu, S., Yi, M., Qin, S., et al.[2020]

CAR-T cell therapy shows promise in treating relapsed or refractory malignancies, particularly in hematological cancers like acute B-cell lymphoblastic leukemia and B-cell lymphomas, with ongoing research into its application for solid tumors.

This systematic review aims to comprehensively assess the safety and efficacy of CAR-T cell therapy by analyzing various studies, focusing on outcomes such as complete response rates and adverse events, to better understand its potential risks and benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. Grigor, EJM., Fergusson, DA., Haggar, F., et al.[2019]

CAR-directed cancer therapy has shown promising results in early clinical trials, particularly in patients with refractory chronic lymphoid leukemia, leading to the disappearance of leukemia cells despite previous treatments.

The technology is also being tested for solid tumors like glioma, with nearly 30 clinical trials currently underway, indicating a significant potential for advancing targeted cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy. Chen, Y., Liu, D.[2022]

Chimeric antigen receptor (CAR) T cell therapy has shown significant promise in treating relapsed or refractory B cell malignancies, achieving durable remissions in both adults and children.

While the permanent genetic modification of T cells appears safe, managing their in vivo function and potential toxicity remains a challenge, leading to the development of new strategies like suicide systems and cytokine blockade to enhance safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of chimeric antigen receptor therapy for haematological malignancies. Maude, S., Barrett, DM.[2016]

Chimeric antigen receptor (CAR)-modified T cells are a promising living immunotherapy that can effectively treat various diseases, particularly refractory cancers like leukemia and lymphoma.

Recent advancements in CAR design and T cell manufacturing have improved the clinical management of patients, leading to lasting remissions and establishing CAR T cell therapy as a leading treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances and Challenges of CAR T Cells in Clinical Trials. Holzinger, A., Abken, H.[2019]

References

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

CD4-Targeted T Cells Rapidly Induce Remissions in Mice with T Cell Lymphoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. [2018]

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

CD19 CAR T cell product and disease attributes predict leukemia remission durability. [2022]

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

Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Simplified process for the production of anti-CD19-CAR-engineered T cells. [2022]

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

Chimeric Antigen Receptor T-Cell Emergencies: Inpatient Administration, Assessment, and Management. [2021]

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

CAR-T Cell Therapy: the Efficacy and Toxicity Balance. [2023]

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

Complete spectrum of adverse events associated with chimeric antigen receptor (CAR)-T cell therapies. [2023]

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

Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. [2020]

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

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. [2019]

11. China pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy. [2022]

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

Current status of chimeric antigen receptor therapy for haematological malignancies. [2016]

13. Germany pubmed.ncbi.nlm.nih.gov

Advances and Challenges of CAR T Cells in Clinical Trials. [2019]