TCR-Transduced T Cells for Blood Cancers

Overseen By Genevieve C Fromm

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: HIV, Acute promyelocytic leukemia, others

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

Compensation: Varies

Number of Visits: 16

86 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for blood cancers with specific genetic mutations, which can complicate treatment. Researchers will modify a patient's T cells (a type of immune cell) to target these cancer-specific markers, aiming to improve treatment outcomes. This approach, known as Individual Patient TCR-Transduced PBL, suits individuals diagnosed with certain blood cancers who have mutations in the TP53 or RAS genes. Participants will undergo blood and skin tests, receive altered T cells, and attend various follow-up visits to monitor progress. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you must not have received systemic chemotherapy for at least 14 days before starting the trial treatment, except for hydroxyurea, which can be taken up to 7 days before apheresis.

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

In a previous study, researchers found that TCR-transduced T cell therapy shows promise in targeting blood cancer cells with specific mutations. These specially modified T cells are designed to find and attack cancer cells without harming healthy ones.

Research indicates that these T cells are precise, mainly targeting the intended cancer cells. Early results from similar studies suggest this approach can be safe and effective, but it's important to remember that this trial is still in its early stages. While there is potential, more information is needed to fully understand the safety for all patients.

Additionally, previous clinical trials with TCR-based therapies have focused on balancing effectiveness and side effects. Some patients may experience side effects, like flu-like symptoms, but these are often manageable.

Overall, while promising evidence exists, participating in such trials means joining a research study where outcomes can vary. Participants should discuss any concerns with their healthcare team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about using TCR-transduced T cells for treating blood cancers because this approach offers a more targeted attack on cancer cells. Unlike traditional chemotherapy, which indiscriminately attacks all rapidly dividing cells, TCR-transduced T cells are engineered to recognize specific cancer-related neoepitopes, allowing for a more precise immune response. Additionally, the infusion of these modified T cells, combined with a preparative regimen and aldesleukin, could potentially enhance the body's ability to fight cancer more effectively. This personalized method aims to improve treatment outcomes while minimizing the side effects commonly associated with standard treatments like chemotherapy and hematopoietic stem cell transplantation.

What evidence suggests that this trial's treatments could be effective for blood cancers?

Research has shown that a new treatment using TCR-transduced T cells holds promise for blood cancers. In this trial, participants will receive a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of neoepitope-specific T cells. This treatment modifies a person's own T cells, part of the immune system, to attack cancer cells with specific markers called neoepitopes. Early results from similar methods suggest these modified T cells can effectively target and destroy cancer cells in patients with hard-to-treat mutations. Although this approach remains under investigation, its personalized nature offers hope for successfully treating blood cancers with specific genetic mutations. ^{2 3 4 6 7}

Who Is on the Research Team?

James N Kochenderfer, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for adults aged 18 to 75 with one of nine specific blood cancers, including various leukemias and myelodysplastic syndromes. Participants must have a confirmed diagnosis with TP53 or RAS mutations. They should be able to undergo procedures like bone marrow biopsy and apheresis.

Inclusion Criteria

-Eligible diagnoses include AML (acute myeloid leukemia), MDS (myelodysplastic syndrome), CMML(chronic myelomonocytic leukemia), CML (chronic myeloid leukemia), and T-ALL (T-acute lymphoblastic leukemia/lymphoma) meeting standard diagnostic criteria as described in the 5th edition World Health Organization Classification of Hematologic Tumors and/or the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Multiple myeloma participants meeting International Working Group diagnostic criteria are eligible. These diagnostic criteria can be met at any time during the course of the participant s malignancy. Atypical CML is not an eligible diagnosis.

NOTE: Pathology reports are acceptable to confirm eligibility.

* Detection of at least one of the neoepitope-forming TP53 or RAS mutations that are listed in Table 3 in on the TruSight Oncology (TSO) 500 sequencing panel (NSR device) performed in the NCI Laboratory of Pathology is required. RAS mutations can be in NRAS, KRAS or HRAS as these oncogenes have the same amino acid sequence at the location of the targeted neoepitopes. A variant allele frequency (VAF) of at least 5% is required for a mutation to be eligible. This criterion can be met at any time within 60 days prior to apheresis regardless of treatment history during this 60-day period. DNA for sequencing comes from bone marrow.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Apheresis

Participants undergo apheresis to collect T cells for modification

1 day

1 visit (in-person)

Chemotherapy Conditioning

Participants receive a chemotherapy conditioning regimen of cyclophosphamide and fludarabine

3 days

T-cell Infusion and Initial Monitoring

Participants receive an infusion of neoepitope-specific T cells and begin aldesleukin infusions, followed by mandatory inpatient hospitalization to monitor for toxicity

7 days

Inpatient stay

Follow-up

Participants are monitored for safety and effectiveness after treatment with 8 follow-up visits in the first year and 6 more visits over the next 4 years

5 years

14 visits (in-person)

Long-term Follow-up

Long-term follow-up to monitor for late effects and overall response

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Individual Patient TCR-Transduced PBL

Trial Overview The study tests altering T cells to target cancer-specific substances called neoepitopes in blood cancers. It involves taking the patient's T cells, modifying them in the lab, then reintroducing them after pre-treatment drugs are administered over three days.

How Is the Trial Designed?

Group I: 2/Experimental: prior allo-HSCT Experimental Treatment 5 Interventions

Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (at a dose of 1x10\^10 total cells) + aldesleukin.

Group II: 1/Experimental: No allo-HSCT Experimental Treatment 5 Interventions

Preparative regimen of cyclophosphamide and fludarabine + infusion of neoepitope-specific T cells (of up to 1.5x10\^11 total cells) + aldesleukin.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a small trial, T cells modified to target the Wilms tumor antigen 1 were effective in preventing relapse in patients with acute myeloid leukemia after they underwent an allogeneic stem-cell transplant.

This approach highlights the potential of engineered T cell therapies in enhancing post-transplant outcomes for leukemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR Gene Therapy Improves AML Prognosis. [2020]

The use of TCR gene-modified T cells shows promise in treating hematological malignancies, as demonstrated in a human trial where these modified cells persisted long-term and reduced tumor burden in some patients.

Targeting the WT1 protein with TCR gene therapy has proven effective in eliminating leukemia cells in mouse models, and advancements in lentiviral TCR gene transfer aim to enhance safety and efficacy by improving TCR expression and reducing mis-pairing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. Stauss, HJ., Thomas, S., Cesco-Gaspere, M., et al.[2022]

A novel T-cell immunotherapy was developed using a transgene that includes a T-cell receptor (TCR) specific for the HA-1 minor H antigen, which is associated with leukemia, aiming to target and eliminate leukemia cells after hematopoietic stem cell transplantation (HCT).

This engineered T-cell product incorporates safety features, such as an inducible caspase 9 switch to remove T-cells if they cause toxicity, and is designed to enhance the persistence and function of T-cells while minimizing the risk of alloreactivity, showing promising functional responses against primary leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse. Dossa, RG., Cunningham, T., Sommermeyer, D., et al.[2022]

Adoptive cell transfer (ACT) using TCR-engineered T cells showed significant antitumor activity in mice with large tumors, especially when combined with lymphodepletion, dendritic cell vaccination, and high-dose IL-2.

The study utilized advanced imaging techniques to track T cell distribution and confirmed that these engineered T cells initially targeted antigen-matched tumors effectively, providing insights that could help translate this therapy for human use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. Koya, RC., Mok, S., Comin-Anduix, B., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6540815/

TCR-based Immunotherapy for Hematologic Malignancies Preclinical studies of TCR-T specific for many other TAAs are underway and offer great promise as safe and effective therapies for a wide range of cancers.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03412877

NCT03412877 | Administration of Autologous T-Cells ... This clinical protocol will treat participants with refractory solid cancers using the adoptive transfer of autologous PBL transduced with genes encoding TCRs ...

3. withpower.com withpower.com/trial/tcr-transduced-t-cells-for-blood-cancers-c0e3e

TCR-Transduced T Cells for Blood Cancers This treatment is unique because it involves modifying a patient's own T cells to specifically target cancer cells by using T cell receptor (TCR) gene transfer.

4. nature.com nature.com/articles/d41573-024-00121-4

TCR-boosted T cell therapy yields proof-of-principle clinical ... TCR-boosted T cell therapy yields proof-of-principle clinical data in solid cancer. By. Asher Mullard. Asher Mullard. View author publications.

5. cgtlive.com cgtlive.com/view/national-cancer-institute-tests-tcr-transduced-t-cell-therapy-solid-tumors-phase-2-trial

National Cancer Institute Tests TCR-Transduced T-Cell ... This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06904066

Study Details | NCT06904066 | Autologous T Cells ... We have shown that the TCRs have activity against hematologic malignancy cell lines in vitro and in vivo and have high specificity for only cells expressing the ...

7. ascopubs.org ascopubs.org/doi/10.1200/EDBK-25-473440

Autologous T-Cell Therapies in Solid Tumor Malignancies Multiple clinical trials examining the maximum tolerated dose, safety, tolerability, and antitumor activity of TCR T-cell therapies with high ...