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

Trial Summary

What is the purpose of this trial?

Background: Blood cancers (such as leukemias) can be hard to treat, especially if they have mutations in the TP53 or RAS genes. These mutations can cause the cancer cells to create substances called neoepitopes. Researchers want to test a method of treating blood cancers by altering a person s T cells (a type of immune cell) to target neoepitopes. Objective: To test the use of neoepitope-specific T cells in people with blood cancers Eligibility: People aged 18 to 75 years with any of 9 blood cancers. Design: Participants will have a bone marrow biopsy: A sample of soft tissue will be removed from inside a pelvic bone. This is needed to confirm their diagnosis and the TP53 and RAS mutations in their cancer cells. They will also have a skin biopsy to look for these mutations in other tissue. Participants will undergo apheresis: Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein. The T cells will be grown to become neoepitope-specific T cells. Participants receive drugs for 3 days to prepare their body for the treatment. The modified T cells will be given through a tube inserted into a vein. Participants will need to remain in the clinic at least 7 days after treatment. Participants will have 8 follow-up visits in the first year after treatment. They will have 6 more visits over the next 4 years. Long-term follow-up will go on for 10 more years.

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.

What data supports the effectiveness of the treatment TCR-Transduced T Cells for Blood Cancers?

Research shows that T cells engineered to express specific receptors can help prevent relapse in blood cancers like acute myeloid leukemia by targeting cancer cells more effectively. This approach has shown promise in reducing the risk of leukemia relapse and providing strong anti-leukemia effects without causing harmful side effects like graft-versus-host disease. ^{1 2 3 4 5}

Is TCR-Transduced T Cell therapy safe for humans?

Research on TCR-Transduced T Cells, used for treating blood cancers, shows that they can be safe when engineered to target specific cancer antigens, with some studies indicating reduced risk of graft-versus-host disease (a condition where donor cells attack the recipient's body) when used early after transplantation. Safety measures, like a built-in safety switch, are also being developed to manage potential toxicities. ^{2 4 6 7 8}

How does the TCR-Transduced T Cells treatment for blood cancers differ from other treatments?

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. This approach enhances the T cells' ability to recognize and attack cancer cells, offering a personalized and potentially more effective treatment compared to standard therapies. ^{3 9 10 11 12}

Research Team

James N Kochenderfer, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

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

Inducible T-cell receptor expression in precursor T cells for leukemia control. [2018]

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

PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells. [2021]

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

CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell receptors improve antitumor T cell function. [2022]

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

TCR Gene Therapy Improves AML Prognosis. [2020]

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

Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses. [2022]

6. Italy pubmed.ncbi.nlm.nih.gov

Clinical practice: chimeric antigen receptor (CAR) T cells: a major breakthrough in the battle against cancer. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors. [2020]

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

Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse. [2022]

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

WT1-specific T cell receptor gene therapy: improving TCR function in transduced T cells. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Generation of diffuse large B cell lymphoma-associated antigen-specific Vα6/Vβ13+T cells by TCR gene transfer. [2021]

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

CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells. [2022]

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

Reconstitution of CD8+ T cells by retroviral transfer of the TCR alpha beta-chain genes isolated from a clonally expanded P815-infiltrating lymphocyte. [2019]