CD4CAR for AML

Overseen By Huda S. Salman

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Huda Salman

Must not be taking: Systemic glucocorticoids, Gene therapy

Disqualifiers: CD4 negative AML, 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: 6

Duration: 4 weeks

30 Participants Needed

Trial Summary

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 high doses of systemic glucocorticoids (steroids) unless they can be safely reduced. You can continue low-dose steroids and inhaled glucocorticoids.

What data supports the effectiveness of the treatment CD4CAR for AML?

Research shows that CD4CAR T cells can specifically target and eliminate CD4-expressing AML cells in lab settings and animal models, suggesting potential effectiveness in treating certain types of AML. ^{1 2 3 4 5}

Is CD4CAR T-cell therapy safe for humans?

The research on CD4CAR T-cell therapy for acute myeloid leukemia (AML) is still in early stages, primarily focusing on preclinical studies. These studies show that CD4CAR T-cells can target and eliminate AML cells in lab settings and animal models, but there is limited information on safety in humans. ^{1 3 6 7 8}

What makes the CD4CAR treatment unique for AML?

CD4CAR treatment is unique for AML because it uses genetically engineered T-cells to specifically target and eliminate CD4-expressing leukemia cells, which are not found on normal stem cells, offering a targeted approach that could serve as a bridge to stem cell transplant. ^{1 2 3 9 10}

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-redirected chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed or refractory AML. The study will evaluate safety in this patient population and also the presence of efficacy signal described by elimination of residual disease to qualify patients for stem cell transplant.

Research Team

Huda Salman, MD, PhD

Principal Investigator

Indiana University

Eligibility Criteria

This trial is for individuals with Acute Myeloid Leukemia (AML) that has come back or hasn't responded to treatment. It's aimed at those who might be candidates for a stem cell transplant if this therapy reduces their disease.

Inclusion Criteria

I can undergo apheresis with no issues.

My lung function test shows a capacity of 60% or more.

My AML is resistant or has come back after initial treatment.

Exclusion Criteria

Active autoimmune diseases requiring systematic treatments

Eligibility for CD4CAR infusion: Afebrile and not receiving antipyretics, and no evidence of active infection. Negative pregnancy testing (if applicable). If previous history of corticosteroid chemotherapy, subject must be off all but adrenal replacement doses 3 days before the CD4CAR infusion. Planned infusion dose was successfully manufactured and met release criteria

I am HIV positive.

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 large numbers of peripheral blood mononuclear cells (PBMC) for the manufacturing of CD4CAR T-cells.

4 weeks

Conditioning Chemotherapy

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

1-2 weeks

Treatment

Participants receive CD4CAR cells by infusion on Day 0 of treatment. Post-infusion monitoring includes blood draws for cytokine levels and CD4CAR Transgene Copy Number.

4 weeks

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

Follow-up

Participants are monitored for safety and effectiveness after treatment, with clinicoradiologic measurements of residual tumor burden and quarterly clinical evaluations.

2 years

Monthly for 6 months, then quarterly

Long-term Follow-up

Participants enter a rollover study to assess for disease-free survival (DFS), relapse, and development of other health problems or malignancies.

13 years

Twice a year by phone and questionnaire

Treatment Details

Interventions

• CD4CAR

Trial Overview The study tests CD4CAR, a type of engineered T-cell therapy designed to target AML cells. This Phase I trial will assess the safety and potential effectiveness of CD4CAR as a preparatory step before a stem cell transplant.

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+

Findings from Research

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-modified T cells, specifically those expressing anti-CD123, have shown effectiveness in treating Acute Myeloid Leukemia (AML) by eradicating AML cells.

This innovative immunotherapeutic approach highlights the potential of genetically modified T cells as a promising strategy in the development of AML treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics? Tettamanti, S., Biondi, A., Biagi, E., et al.[2022]

CAR T-cell therapy for acute myeloid leukemia (AML) faces challenges due to the lack of specific surface antigens, but advancements are being made to improve its effectiveness.

Potential strategies to enhance the safety and efficacy of CAR T-cell therapy for AML include reducing the potency of CAR T cells, using transient CAR T cells during pre-transplant conditioning, and employing gene-edited allogeneic stem cell transplants to support sustained anti-AML activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How close are we to CAR T-cell therapy for AML? Gill, SI.[2021]

Chimeric antigen receptor (CAR)-modified immune effector cell therapies show promise for treating acute myeloid leukemia (AML), similar to their success in B-cell malignancies, but translating this success is challenging due to the need for suitable target antigens and managing potential toxicities.

The review highlights the importance of identifying leukemia-restricted target antigens and strategies to enhance the effectiveness of CAR therapies while minimizing side effects in the immunosuppressive environment of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor (CAR)-Modified Immune Effector Cell Therapy for Acute Myeloid Leukemia (AML). Acharya, UH., Walter, RB.[2023]

CAR T-cell therapy shows promise in improving outcomes for patients with acute myeloid leukemia (AML), a condition with historically poor prognosis.

A significant challenge for the effectiveness of CAR T-cell therapy in AML is the identification of specific target antigens on leukemia cells, as well as the risk of immune escape due to changes in these antigens and a suppressive tumor environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current challenges for CAR T-cell therapy of acute myeloid leukemia. Sauer, T., Rooney, CM.[2020]

CAR-T cell therapy has shown promise in treating aggressive hematologic malignancies like acute myeloid leukemia (AML), but its clinical application faces challenges due to the antigenic diversity of AML, which complicates target selection.

Key obstacles for effective CAR-T therapy in AML include the risk of on-target off-tumor toxicities and the unique characteristics of the AML tumor microenvironment, which need to be addressed in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success. Fiorenza, S., Turtle, CJ.[2021]

CAR T-cell therapy has shown great success in treating B-cell malignancies but faces challenges in effectively targeting myeloid malignancies like acute myeloid leukemia (AML).

Current research is focused on identifying specific target antigens for myeloid leukemia stem cells to improve CAR T-cell therapy's efficacy while reducing harm to healthy blood cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-cell Therapy for Acute Myeloid Leukemia. Bi, X., Hsu, J., Gergis, M., et al.[2022]

The study identifies LILRB4 as a promising tumor-associated antigen specifically expressed on monocytic acute myeloid leukemia (AML) cells, allowing for targeted therapy without affecting normal blood stem cells.

The novel anti-LILRB4 CAR-T cells demonstrated effective targeting and destruction of LILRB4+ AML cells in laboratory tests, while showing no toxicity to normal hematopoietic progenitors, suggesting a safer treatment option for patients with monocytic AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML. John, S., Chen, H., Deng, M., et al.[2020]

The study demonstrates the successful engineering of cytokine-induced killer (CIK) cells with a CD33 chimeric antigen receptor (CAR) using an optimized non-viral transposon system, which enhances CAR expression and reduces DNA transposase requirements.

CD33.CAR-CIK cells showed significant anti-leukemic effects in both in vitro and in vivo models, effectively targeting chemotherapy-resistant acute myeloid leukemia (AML) cells, indicating their potential for integration into existing treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System. Rotiroti, MC., Buracchi, C., Arcangeli, S., et al.[2021]

CD93 has been identified as a promising target antigen for chimeric antigen receptor T-cell therapy in treating acute myeloid leukemia (AML).

The study also presents a strategy to reduce the risk of 'on-target/off-cancer toxicity,' which is a significant concern in targeted cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Employing Synthetic T-cell Biology to Target AML without On-Target/Off-Cancer Toxicity. Velasquez, MP., Gottschalk, S.[2023]

References

1. 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]

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

CD123 AML targeting by chimeric antigen receptors: A novel magic bullet for AML therapeutics? [2022]

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

How close are we to CAR T-cell therapy for AML? [2021]

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

Chimeric Antigen Receptor (CAR)-Modified Immune Effector Cell Therapy for Acute Myeloid Leukemia (AML). [2023]

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

Current challenges for CAR T-cell therapy of acute myeloid leukemia. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success. [2021]

7. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-cell Therapy for Acute Myeloid Leukemia. [2022]

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

A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML. [2020]

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

Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System. [2021]

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

Employing Synthetic T-cell Biology to Target AML without On-Target/Off-Cancer Toxicity. [2023]