Genetically Modified T Cells for Acute Myeloid Leukemia

Overseen By EmergingMed

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Pregnancy, HIV, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 3 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial researches a new treatment for people with acute myeloid leukemia (AML), a type of blood cancer. The study tests genetically modified T cells, called CART123 cells (Chimeric Antigen Receptor T-123 cells), to determine their safety and effectiveness. Participants should have AML that hasn't responded to other treatments or has returned after a stem cell transplant. The trial aims to offer hope for those without other curative options. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, providing participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not allow the use of systemic steroids or immunosuppressant medications, so you would need to stop these if you are currently taking them. However, inhaled steroids or physiologic replacement with hydrocortisone are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CART123 cells might help treat acute myeloid leukemia (AML). Studies have found that patients whose AML has returned or not responded to other treatments have shown improvement with this therapy. Earlier research on these modified T cells was safe enough to lead to more trials.

Regarding safety, patients treated with CART123 cells have experienced manageable side effects. These include common reactions to CAR T-cell therapies, such as fever and low blood counts, which are usually temporary and treatable.

The CART123 treatment is in an early stage of clinical trials, focusing mainly on safety. More detailed safety information will become available as more patients try the treatment. The initiation of this phase suggests that earlier studies found it safe enough for human testing.

Overall, early results suggest that CART123 cells are generally well-tolerated, with side effects similar to those of other CAR T-cell therapies. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard chemotherapy treatments like cytarabine and daunorubicin for acute myeloid leukemia (AML), CART123 cells offer a novel approach by using genetically modified T cells to specifically target and attack cancer cells. This treatment harnesses the power of the immune system, potentially leading to more precise and effective cancer cell elimination. Researchers are excited about CART123 cells because they represent a shift towards personalized medicine, promising a targeted attack on leukemia cells while sparing healthy cells, which could mean fewer side effects compared to traditional chemotherapy.

What evidence suggests that this trial's treatments could be effective for Acute Myeloid Leukemia?

Research has shown that CAR-T therapy, such as CART123 cells, could be a promising treatment for acute myeloid leukemia (AML), particularly for patients whose cancer has returned or hasn't responded to other treatments. In this trial, participants will receive CART123 cells combined with cyclophosphamide and fludarabine. Studies have found that CART123 cells can locate and attack cancer cells by recognizing a specific protein called CD123. Although results for AML are not as successful as those for acute lymphoblastic leukemia (ALL), the therapy remains hopeful for high-risk AML cases. CART123 cells use specially modified immune cells, called T cells, to seek out and destroy cancer cells. The treatment poses challenges due to the complexity of AML, but early research suggests it could be a valuable option for some patients. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults with Acute Myeloid Leukemia (AML) who haven't achieved remission or have relapsed, including after stem cell transplants. They must be over 18, have good organ function and performance status, not pregnant or breastfeeding, without severe active infections like HIV or hepatitis B/C, no history of certain heart conditions or other specific diseases.

Inclusion Criteria

My organs are functioning well.

- Creatinine ≤ 1.6 mg/dl

- ALT/AST must be ≤5 x upper limit of normal unless related to disease

Exclusion Criteria

I am HIV positive.

I do not have unstable heart rhythm issues.

My AML has returned and has a specific genetic feature (t(15:17)).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine prior to CART123 cell infusion

1 week

Treatment

Participants receive CART123 cell infusion with a split dosing approach or single administration

3 days

Follow-up

Participants are monitored monthly for safety and efficacy for up to 6 months post-infusion

6 months

Long-term Follow-up

Participants are transitioned into long-term follow-up for up to 15 years post-infusion

15 years

What Are the Treatments Tested in This Trial?

Interventions

• CART123 cells
• Cyclophosphamide
• Fludarabine

Trial Overview The study tests a new therapy where patients' T cells are modified to target AML cells and then put back into the body. It's combined with two chemotherapy drugs: cyclophosphamide and fludarabine. The goal is to see if this approach is safe and effective against AML.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 1 Intervention

CART123 cells; cyclophosphamide; fludarabine

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

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]

CD123 is confirmed as a valid target for treating acute myeloid leukemia (AML), with both 41BB-based and CD28-based CAR T-cell therapies showing strong effectiveness in eliminating AML cells in laboratory and animal models.

However, these CAR T-cell therapies also destroy normal blood stem cells, which raises safety concerns and suggests they should primarily be used as a temporary solution before a stem cell transplant in patients with refractory or relapsed AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. Baroni, ML., Sanchez Martinez, D., Gutierrez Aguera, F., et al.[2021]

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]

Genetically engineered T cells expressing chimeric antigen receptors (CARTs) have shown remarkable efficacy in treating relapsed/refractory acute lymphoblastic leukaemia (ALL), achieving not only remission but also long-term disease control.

Ongoing research aims to enhance the efficacy and safety of CART therapy, expanding its applicability to other types of cancers beyond leukaemias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise of chimeric antigen receptor T cells (CARTs) in leukaemia. Orlowski, RJ., Porter, DL., Frey, NV.[2018]

CART33, a chimeric antigen receptor T cell therapy targeting CD33, showed significant effectiveness in eradicating acute myeloid leukemia (AML) in preclinical models, leading to prolonged survival.

To reduce the risk of long-term toxicity associated with permanent CART cell expression, a transiently expressed mRNA anti-CD33 CAR was developed, demonstrating potent but self-limited activity against AML, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Kenderian, SS., Ruella, M., Shestova, O., et al.[2022]

CD123 chimeric antigen receptor (CAR) redirected T cells have shown strong antileukemic activity, indicating a promising new approach for treating acute myeloid leukemia.

The development of CD123 CARs provides insights into enhancing immunotherapy strategies, highlighting the need for novel treatments in this challenging disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myeloid leukemia therapeutics: CARs in the driver's seat. Mardiros, A., Brown, CE., Budde, LE., et al.[2021]

CAR T-cell therapy has the potential to improve outcomes for patients with acute myeloid leukemia (AML) by specifically targeting leukemia cells, but there are significant challenges to its effectiveness and safety.

Strategies being explored to enhance CAR T-cell therapy in AML include targeting specific leukemia antigens to reduce side effects, using checkpoint inhibitors to counteract immune suppression caused by leukemia, and developing allogenic CAR T cells to make the treatment more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospect of CAR T-cell therapy in acute myeloid leukemia. Badar, T., Manna, A., Gadd, ME., et al.[2022]

Adoptive transfer of genetically engineered T cells has shown significant and lasting responses in patients with blood cancers, highlighting its potential as a powerful treatment option.

The success of this therapy relies heavily on the quality of T cells produced, which is influenced by the methodologies and reagents used in their generation for preclinical studies, particularly in the context of chimeric antigen receptor T cell therapy for acute myeloid leukemia (AML).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generating and Expanding Autologous Chimeric Antigen Receptor T Cells from Patients with Acute Myeloid Leukemia. Kenderian, SS., June, CH., Gill, S.[2018]

CD123 is identified as a promising target for CAR T-cell therapy in acute myeloid leukemia (AML), as its expression increases over time in tumor cells, making it a viable option for treatment.

While CART123 T cells effectively eliminate AML cells in mice, they also destroy normal blood cell production, highlighting the need for careful management and potential rescue strategies during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Gill, S., Tasian, SK., Ruella, M., et al.[2021]

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]

Citations

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T cells expressing CD123 chimeric antigen receptors for ... CD123 CAR T cell based immunotherapy is a promising treatment for patients with relapsed or refractory acute myeloid leukemia.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10164930/

Outcomes with chimeric antigen receptor t-cell therapy in ... CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable ...

3. cell.com cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(25)00261-8

CAR-T cell therapy for treatment of acute myeloid leukemia ... The success of chimeric antigen receptor T (CAR-T) cell therapy in acute lymphoblastic leukemia (ALL) has not yet been replicated in AML. There ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02623582

NCT02623582 | CD123 Redirected Autologous T Cells for ... Pilot open-label study to estimate the feasibility, safety and efficacy of intravenously administered, RNA electroporated autologous T cells expressing anti-CD ...

5. ashpublications.org ashpublications.org/blood/article/122/18/3138/31813/T-cells-expressing-CD123-specific-chimeric-antigen

T cells expressing CD123-specific chimeric antigen receptors ... These results suggest that CD123 CAR T cells are a promising immunotherapy for the treatment of high-risk AML. Subjects: Gene Therapy, Immunobiology and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04014881

NCT04014881 | Safety and Efficacy of Anti-CD123 CAR-T ... This study aims to evaluate the safety and efficacy of anti-CD123 CAR-T cells in patients with relapsed/refractory CD123+ Acute Myeloid Leukemia. Official Title.

7. sciencedirect.com sciencedirect.com/science/article/pii/S014521262400064X

Safety and efficacy of chimeric antigen receptor T-cell ... This meta-analysis highlights the potential of CAR T-cell therapy in AML treatment, especially when integrated with certain prior treatments and conditioning ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6601074/

Chimeric antigen receptor T-cell therapy for acute myeloid ... This favorable safety data paved the way for a phase I trial of lentivirally-transduced second-generation CART123 (CD123CAR-41BB-CD3ζ) which has begun ...

9. ashpublications.org ashpublications.org/blood/article/123/15/2343/32257/Preclinical-targeting-of-human-acute-myeloid

Preclinical targeting of human acute myeloid leukemia and ... We show that CD123 is a good target for AML-directed CAR therapy, because its expression increases over time in vivo even in initially CD123 dim populations.