CAR T Cell Therapy for Chronic Myelomonocytic Leukemia

Recruiting at 3 trial locations

Overseen By Huda S. Salman

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Huda Salman

Must not be taking: Systemic glucocorticoids, Immunosuppressive drugs

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: Unknown

Duration: 4 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CD4CAR T-cell therapy, which uses a patient's modified immune cells to target chronic myelomonocytic leukemia (CMML) that hasn't responded to standard treatments. The main goal is to determine if this treatment is safe and feasible for people with this type of cancer. The trial seeks participants with CD4+ CMML that has not responded to first-line treatment. Participants should have a history of CMML affecting their daily life and should not have other active infections or serious health conditions. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you must stop all current medications, but you cannot use high doses of systemic glucocorticoids (steroids) unless they can be safely reduced. Inhaled steroids are allowed, and some replacement doses of corticosteroids are permitted.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that CD4CAR T-cell therapy remains in the early stages of testing for safety in humans. As a phase 1 study, the primary goal is to determine the treatment's safety and potential side effects.

While specific information on CD4CAR T-cells is limited, similar CAR T-cell therapies have been used for other conditions, showing common side effects such as fevers, fatigue, and low blood counts. However, the safety details for CD4CAR T-cells in treating chronic myelomonocytic leukemia (CMML) are not yet fully understood.

The study will closely monitor participants to assess their response to the treatment. As a phase 1 trial, researchers will carefully observe any unexpected side effects and adjust doses to identify the safest amount to administer. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for chronic myelomonocytic leukemia, which often involve chemotherapy or hypomethylating agents, CD4CAR represents a novel approach by using genetically engineered T cells. CD4CAR cells are autologous T cells that have been modified with an anti-CD4 lentiviral vector, enabling them to specifically target and attack cancer cells expressing the CD4 protein. This targeted mechanism not only offers the potential for greater precision and effectiveness but also reduces the likelihood of harming healthy cells. Researchers are excited about CD4CAR because it leverages the body's own immune system to fight the disease, which could lead to more sustainable and less toxic treatment options.

What evidence suggests that CD4CAR T cells might be an effective treatment for CMML?

Research has shown that CD4CAR T cells, which participants in this trial will receive, are designed to find and attack cancer cells in chronic myelomonocytic leukemia (CMML). These cells specifically recognize and attach to the CD4 protein on certain cancer cells. Early results suggest that CD4CAR T cells can enhance the body's immune response against these cancer cells. Previous studies have found that similar CAR T cell treatments can significantly reduce tumors in other blood cancers. While specific results for CD4CAR T cells in CMML are still under investigation, their mechanism suggests they could be highly effective. ^{1 2 3 4 6}

Who Is on the Research Team?

Huda Salman, MD, PhD

Principal Investigator

Indiana University

Are You a Good Fit for This Trial?

Adults with Chronic Myelomonocytic Leukemia (CMML) that has come back or didn't respond to first treatments can join. They must have normal liver and kidney function, good heart health, and no serious mental disorders or drug abuse history. Pregnant women, those with active hepatitis B/C, HIV, other cancers needing recent treatment, uncontrolled infections or autoimmune diseases requiring systemic therapy are excluded.

Inclusion Criteria

Your Pulmonary Function Test (PFT) must have a DLCO measurement of 60% or higher, and if the test was done within 45 days prior to initial assessment it will not need to be repeated.

My CMML is resistant to initial treatments and tests positive for CD4.

Your echocardiogram must demonstrate an ejection fraction of at least 50%, and will not need to be redone if it has been performed in the last 45 days.

Exclusion Criteria

I am not pregnant or breastfeeding, and I have a negative pregnancy test.

I have never received gene therapy treatments.

I have not received any live vaccines within 30 days before starting the trial, except for the flu shot.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Leukapheresis and Manufacturing

Qualifying subjects will be leukapheresed to obtain peripheral blood mononuclear cells for manufacturing CD4CAR T-cells.

2-4 weeks

Conditioning Chemotherapy

Participants receive conditioning chemotherapy to reduce tumor burden before CD4CAR infusion.

1 week

Treatment

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

4 weeks

Visits on days 0, 1, 3, 5, 7, 14, and 28

Follow-up

Participants are monitored for safety and effectiveness, including clinicoradiologic measurements and blood tests.

6 months

Monthly visits

Long-term Follow-up

Quarterly clinical evaluations for two years, followed by biannual assessments for an additional thirteen years.

15 years

What Are the Treatments Tested in This Trial?

Interventions

• CD4CAR

Trial Overview The trial is testing a new type of T-cell therapy called CD4CAR for people whose CMML has relapsed or is resistant to initial treatments. It's an early-phase study focusing on the safety and practicality of using these engineered T-cells in patients.

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

Lead Sponsor

Trials

3

Recruited

80+

iCell Gene Therapeutics

Industry Sponsor

Trials

15

Recruited

270+

The Leukemia and Lymphoma Society

Collaborator

Trials

87

Recruited

26,200+

Published Research Related to This Trial

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 T cells have shown early success in treating blood cancers, indicating their potential as an effective immunotherapy.

In solid tumors, CAR T cells face challenges due to a suppressive tumor environment that can limit their effectiveness in fighting cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment. Beatty, GL., Moon, EK.[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]

CAR T cell therapy has shown remarkable success in treating B-cell malignancies, but it faces significant challenges when targeting solid tumors due to the unique characteristics of their microenvironments.

Recent advancements in CAR T cell engineering aim to overcome these challenges by developing smarter CAR T cells that enhance efficacy and reduce adverse effects, paving the way for improved cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells. Elahi, R., Khosh, E., Tahmasebi, S., et al.[2019]

A new CAR immunotherapy targeting CD4 has been developed using NK-92 cells, showing strong effectiveness in eliminating CD4+ T-cell leukemia and lymphoma cell lines, as well as patient samples in laboratory tests.

In animal models, CD4CAR NK-92 cells significantly improved survival by effectively targeting and destroying difficult-to-access lymphoma nodules, suggesting a promising new treatment strategy for aggressive peripheral T-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Pinz, KG., Yakaboski, E., Jares, A., et al.[2023]

Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells show promise in treating blood cancers, particularly with CD19-CAR-T cells demonstrating strong clinical responses in B-cell malignancies.

To enhance the effectiveness and safety of these therapies, researchers are exploring new antigens, improved T cell culture methods, and better administration protocols to address issues like treatment failure and toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming key challenges in cancer immunotherapy with engineered T cells. Arcangeli, S., Mestermann, K., Weber, J., et al.[2021]

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 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 therapy shows significant efficacy in treating hematological malignancies, but it is associated with high rates of hematological toxicity, with 80% of patients experiencing any grade of neutropenia, 61% thrombocytopenia, and 68% anemia based on a meta-analysis of 52 studies involving 2004 patients.

Severe hematological toxicities (grade ≥3) were notably high, with 60% experiencing neutropenia, 33% thrombocytopenia, and 32% anemia, particularly in younger patients and those with a history of multiple prior therapies, highlighting the need for careful monitoring and intervention to prevent life-threatening complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis. Luo, W., Li, C., Zhang, Y., et al.[2022]

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]

CD4 is identified as a promising target for CAR-T cell therapy in treating acute myeloid leukemia (AML), as it is expressed in certain AML subtypes but not on normal hematopoietic stem cells, allowing for targeted treatment.

CD4 redirected CAR-T cells effectively eliminated CD4-expressing AML cells in laboratory settings and demonstrated strong anti-leukemic effects in a mouse model, suggesting potential for clinical application in refractory AML cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. Salman, H., Pinz, KG., Wada, M., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06071624

NCT06071624 | Chimeric Antigen Receptor T Cell Therapy ... 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)

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06071624?term=AREA%5BBasicSearch%5D(AREA%5BConditionSearch%5D(Chronic%20myelomonocytic%20leukemia%20OR%20%22chronic%20myelomonocytic%20leukaemia%20(CMML)%22%20OR%20%22%20chronic%20myelomonocytic%20leukemia%20(CMML)%22%20OR%20%22%20CMML%22)%20AND%20AREA%5BOverallStatus%5D(NOT_YET_RECRUITING%20OR%20RECRUITING))&rank=2

NCT06071624 | Chimeric Antigen Receptor T Cell Therapy ... The study will utilize autologous CD4CAR T-cells that are engineered to express a chimeric antigen receptor (CAR) targeting CD4 that is linked to the cluster of ...

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/425995

Chimeric Antigen Receptor T Cell Therapy Redirected to ... Outcome measure. The efficacy of treatment with CD4CAR and description of CMML response to CD4CAR · Measure description. serial marrow sampling ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-01323

CD4CAR T Cell Therapy for the Treatment of Patients with ... This phase I trial tests the safety, side effects, best dose, and effectiveness of CD4CAR T cell therapy in treating patients with CD4 positive chronic ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9809278/

CD4 CAR-T cells targeting CD19 play a key role in ... CD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of ...

6. medsearchglobal.com medsearchglobal.com/antistudydetail/NCT06071624

Chronic Myelomonocytic Leukemia - NCT06071624 The study will utilize autologous CD4CAR T-cells that are engineered to express a chimeric antigen receptor (CAR) targeting CD4 that is linked to the cluster of ...