CAR T Cell Therapy for Chronic Myelomonocytic Leukemia

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

Trial Summary

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.

What data supports the effectiveness of the treatment CD4CAR T cells for Chronic Myelomonocytic Leukemia?

Research shows that CD4CAR T cells have been effective in targeting and eliminating CD4-expressing cancer cells in other blood cancers like T-cell lymphomas and acute myeloid leukemia in laboratory and animal studies. This suggests potential for similar effectiveness in treating Chronic Myelomonocytic Leukemia, which may also involve CD4-expressing cells. ^{1 2 3 4 5}

Is CAR T cell therapy safe for humans?

CAR T cell therapy, while promising for treating certain cancers, can have serious side effects. These include cytokine release syndrome (CRS), which is a severe immune reaction, and neurotoxicity, which affects the nervous system. Researchers are working on ways to reduce these risks. ^{6 7 8 9 10}

How is the treatment CD4CAR T cells unique for chronic myelomonocytic leukemia?

CD4CAR T cells are a novel treatment that uses genetically engineered T cells to specifically target and eliminate CD4-expressing cancer cells, which is different from traditional therapies that may not target specific markers on cancer cells. ^{1 2 3 5 11}

What is the purpose of this trial?

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) in patients with relapsed or refractory CMML. Specifically, the study will evaluate the safety and feasibility of CD4CAR T-cells.

Research Team

Huda Salman, MD, PhD

Principal Investigator

Indiana University

Eligibility Criteria

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

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

Treatment Details

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.

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

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+

Findings from Research

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]

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]

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]

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]

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 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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

2. Australia pubmed.ncbi.nlm.nih.gov

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. [2020]

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

Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment. [2022]

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

Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. [2023]

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

Overcoming key challenges in cancer immunotherapy with engineered T cells. [2021]

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

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

7. England pubmed.ncbi.nlm.nih.gov

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

8. England 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. [2022]

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. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Cell Hacking: Challenges and Clinical Approaches to Create Smarter Generations of Chimeric Antigen Receptor T Cells. [2019]