CAR T-Cell Therapy for Leukemia and Lymphoma

Recruiting at 6 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called CD4CAR T-cell therapy for individuals with certain blood cancers, such as T-cell leukemia and lymphoma, that have returned or not responded to other treatments. The main goal is to determine if this therapy is safe and can be applied effectively. It is open to those with CD4+ T-cell blood cancers that have not improved with standard treatments or have relapsed. As a Phase 1 trial, the research focuses on safety and understanding patient responses to the treatment. Participants have the opportunity to be among the first to receive this new therapy.

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 there any evidence suggesting that CD4CAR T-cell therapy is likely to be safe for humans?

Research has shown that CD4CAR T-cell therapy could be promising for treating certain types of leukemia and lymphoma. In a study, these specially designed T-cells effectively attacked harmful cells in the body and were generally well-tolerated by patients. Specifically, two out of three patients in that study achieved complete remission, with their cancer no longer detectable, while the third patient showed significant improvement.

This is a Phase 1 trial, marking the first time this treatment is tested in humans to assess safety. Consequently, information on side effects remains limited, but early results are encouraging. So far, no major safety concerns have emerged, suggesting the treatment might be safe, though further research is needed to confirm this. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for leukemia and lymphoma, which often involve chemotherapy or radiation, CD4CAR therapy is unique because it uses genetically modified T cells to target cancer cells more precisely. This treatment works by redirecting the patient's own immune cells, modified with an anti-CD4 lentiviral vector, to specifically attack cancer cells, potentially leading to fewer side effects than traditional methods. Researchers are excited about CD4CAR because it represents a personalized approach to cancer therapy, offering hope for more effective and tailored treatment outcomes.

What evidence suggests that CD4CAR T cells might be an effective treatment for leukemia and lymphoma?

Research has shown that CD4CAR T-cell therapy, the treatment under study in this trial, could be promising for treating blood cancers like leukemia and lymphoma. This treatment uses specially altered T-cells to find and destroy cancer cells. One study found that patients with chronic lymphocytic leukemia experienced long-lasting remission, with some remaining cancer-free for 10 years. Other research on similar CAR-T therapies has demonstrated their effectiveness and general safety for patients whose blood cancers have returned or are not responding to other treatments. CD4CAR specifically targets CD4-expressing cells, which are often present in these cancers. ^{1 6 7 8 9}

Who Is on the Research Team?

Huda Salman, MD

Principal Investigator

Indiana University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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]

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]

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-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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03829540

NCT03829540 | CD4CAR for CD4+ Leukemia and ... 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)

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37890589/

Real-World Outcomes with Chimeric Antigen Receptor T ... Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1465324925007145

CD8 and CD4 CAR-T cells are associated with outcome ... Here, we show that robust expansion of CD8 + CAR-T cells was associated with early response and better long-term survival.

4. nature.com nature.com/articles/s41409-023-02016-1

CD4+ CAR T-cell expansion is associated with response ... In two patients with chronic lymphocytic leukemia, persistence of CD4+ CAR T-cells was associated with 10-year remission of leukemia [8].

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5762550/

Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells In our study, we provide novel targeting of CD4 using CAR-modified NK cells. Indeed, CD4CAR NK-92 cells specifically and effectively target CD4-expressing ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-10831

CD4-Directed Chimeric Antigen Receptor T-cells for the ... This phase I trial tests the safety, side effects, and best dose of CD4-directed chimeric antigen receptor engineered T cells (CD4CAR) in treating patients ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26526988/

Preclinical targeting of human T-cell malignancies using ... These studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to ...

8. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6854/506262/Phase-I-First-in-Human-Study-on-the-Feasibility

Phase I First-in-Human Study on the Feasibility, Safety, and ... CD4CAR T-cell therapy is feasible in patients with R/R CD4+ TCM. 2/3 patients achieved CR and the third achieved hematological CR with stable skin disease.

9. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06071624/chimeric-antigen-receptor-t-cell-therapy-redirected-to-cd4-cd4caras-a-second-line-treatment-for-chronic-myelomonocytic-leukemia-cmml

Chimeric Antigen Receptor T Cell Therapy Redirected to ... This study is designed as a single arm open label traditional Phase I, 3+3, study of CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR)