Genetically Modified T Cells for Solid Tumors

Overseen By Marcus Butler

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: University Health Network, Toronto

Must be taking: Cyclophosphamide, Fludarabine

Must not be taking: Immunosuppressives

Disqualifiers: Autoimmune, Inflammatory bowel, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety of a new treatment, TBI-1301, for individuals with advanced solid tumors, such as ovarian or lung cancer, that express a specific protein called NY-ESO-1. Researchers modify a person's own T cells (a type of immune cell) to potentially help the body attack and kill cancer cells. Participants may qualify if they have a solid tumor that cannot be surgically removed, have tried other treatments without success, and test positive for the NY-ESO-1 protein. The trial includes two groups: one receiving a single infusion of modified T cells and another receiving two infusions. As a Phase 1 trial, this 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 cannot have had anti-cancer treatments like chemotherapy, radiation, or immunotherapy within 2 weeks before the trial. Also, you should not be on immunosuppressive medication within 14 days before the trial, except for certain low-dose steroids.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that TBI-1301, a treatment tested for advanced solid tumors, is generally safe and well-tolerated. Studies found that patients did not experience severe side effects requiring dose adjustments. Some patients experienced mild to moderate cytokine release syndrome (CRS), where the immune system becomes overly active, but it was manageable. Two patients required tocilizumab, a medication that calms the immune system. This suggests that while some side effects may occur, they are usually not serious and can be treated effectively. Overall, evidence indicates that TBI-1301 is safe enough for continued testing in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about TBI-1301 because it offers a novel approach to treating solid tumors by using genetically modified T cells. Unlike traditional treatments like chemotherapy and radiation, which can affect both cancerous and healthy cells, TBI-1301 targets specific cancer cells, potentially reducing harmful side effects. Additionally, this treatment involves the infusion of a large number of modified T cells designed to seek out and destroy tumor cells, providing a targeted immune response. The double infusion strategy in one treatment arm also allows for a sustained attack on the tumor, which may enhance its effectiveness compared to single-dose treatments.

What evidence suggests that TBI-1301 might be an effective treatment for advanced solid tumors?

Studies have shown that TBI-1301, a treatment using specially modified immune cells, effectively targets certain advanced solid tumors. In this trial, participants will receive TBI-1301 in different treatment arms. Specifically, research found that TBI-1301 had a higher success rate for some cancers compared to standard treatments. TBI-1301 targets a specific protein called NY-ESO-1, present in various tumors like ovarian and lung cancer. This targeting allows immune cells to specifically attack and potentially destroy cancer cells. Early research in mice demonstrated that these modified immune cells are both safe and effective, offering hope for human treatments. ^{1 3 5 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors expressing NY-ESO-1, including lung, ovarian, and liver cancers. Participants must have a specific immune system marker (HLA-A*02:01 or HLA-A*02:06), an ECOG status of 0 or 1 indicating they are fully active or restricted in physically strenuous activity but ambulatory, measurable disease progression post-treatment, and adequate organ function. Pregnant women and those with autoimmune diseases, uncontrolled infections, recent immunosuppressants use (except certain steroids), HIV/HTLV/syphilis/hepatitis B/C infections are excluded.

Inclusion Criteria

My kidney function is normal.

Platelets ≥ 75x10^9/L (75,000/μl)

Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤2.5X if Gilbert's disease)

Exclusion Criteria

You have a history of a weakened immune system from birth.

Pregnant women are excluded.

I have or had Crohn's disease or ulcerative colitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

T Cell Manufacturing

Participants' T cells are collected and sent to a laboratory to be genetically modified

4 weeks

Pre-treatment

Participants receive cyclophosphamide and fludarabine intravenously for 2 days

1 week

Treatment

Participants receive TBI-1301 cell infusion on Day 0, with a possible second infusion on Day 14

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• TBI-1301

Trial Overview The study tests TBI-1301 therapy where patients' own T cells are genetically modified to target cancer cells expressing the NY-ESO-1 antigen. The safety of these engineered T cells will be evaluated along with their effect on tumor size using RECIST v1.1 criteria after pre-treatment with cyclophosphamide and fludarabine.

How Is the Trial Designed?

Group I: Cohort C (double infusion) Experimental Treatment 3 Interventions

Cyclophosphamide will be given intravenously (by vein) at a fixed dose of 750mg/m\^2/d for 2 days. Fludarabine will be given intravenously at a fixed dose of 30mg/m\^2/d for 2 days. TBI-1301 cells will be infused on Day 0 and Day 14 at a dose of 5x10\^9 cells.

Group II: Cohort B (retreatment) Experimental Treatment 3 Interventions

Cyclophosphamide will be given intravenously (by vein) at a fixed dose of 750mg/m\^2/d for 2 days. Fludarabine will be given intravenously at a fixed dose of 30mg/m\^2/d for 2 days. TBI-1301 cells will be infused on Day 0 at a dose of 5x10\^9 cells. \*Patients will only enter into this cohort if they have already been enrolled in another cohort prior

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Takara Bio Inc.

Industry Sponsor

Trials

14

Recruited

270+

Published Research Related to This Trial

CAR T cells engineered to target the tumor-associated glycoprotein-72 (TAG72) and modified with membrane-bound IL-12 (mbIL12) show enhanced anti-tumor activity and improved T cell proliferation, demonstrating significant efficacy in human ovarian cancer models.

The use of mbIL12 in CAR T cells not only promotes effective tumor cell killing but also positively impacts the immunosuppressive tumor microenvironment, suggesting a promising approach for treating both local and systemic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Lee, EHJ., Murad, JP., Christian, L., et al.[2023]

T cells play a crucial role in fighting cancer, and recent advances in immunotherapy are focusing on enhancing their effectiveness through genetic engineering.

The introduction of tumor-specific receptors, such as Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), shows promise in ongoing clinical trials, indicating a potential for strong anti-tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle CARs and TcRs: turbo-charged technologies for the (T cell) masses. Kalos, M.[2012]

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has shown significant promise in treating metastatic melanoma, leading to the development of genetically engineered T cells that can specifically target tumor-associated antigens (TAAs).

Initial clinical studies indicate that these genetically engineered T cells, including those with tumor antigen-specific T cell receptors (TCRs) and chimeric antigen receptors (CARs), can effectively cause tumor regression, although safety concerns, particularly regarding potential 'on-target, off-organ' toxicity, must be carefully managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. Shi, H., Liu, L., Wang, Z.[2020]

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

Genetically modifying human T lymphocytes to express chimeric antigen receptors allows them to specifically target and bind to erbB2-positive tumor cells, leading to effective tumor cell lysis.

In preclinical studies, these modified T cells not only produced high levels of cytokines but also significantly delayed the growth of erbB2-positive tumors in human xenograft models, indicating a promising therapeutic strategy for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive antitumor immunotherapy in vitro and in vivo using genetically activated erbB2-specific T cells. Wang, C., Hu, W., Shen, L., et al.[2017]

The study developed optimized CAR T cells targeting TAG72, showing that the CD28 transmembrane domain enhances anti-tumor activity and IFNγ secretion, which is crucial for effective treatment of solid tumors like advanced ovarian cancer.

In preclinical models, CAR T cells expressing a membrane-bound IL-12 (mbIL12) significantly improved T cell proliferation and tumor cell killing, leading to strong anti-tumor responses and better T cell persistence, suggesting a promising approach for enhancing CAR T cell therapies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Jun Lee, EH., Cullen, C., Murad, JP., et al.[2023]

TCR-T cell therapy shows great promise for treating solid tumors by recognizing a wider range of target antigens compared to CAR-T cells, which are primarily effective against CD19+ B cell-derived cancers.

Currently, there are 56 clinical trials worldwide investigating the efficacy of TCR-T cell therapy, highlighting the growing interest and potential for this approach in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer immunotherapy with lymphocytes genetically engineered with T cell receptors for solid cancers. Chen, L., Qiao, D., Wang, J., et al.[2020]

Genetic modification of T cells to express receptors specific for tumor-associated antigens can redirect their function, enhancing their ability to target and eliminate tumor cells, which is crucial for treating common cancers.

Recent advances in gene design and cell production techniques have improved the clinical application of this adoptive immunotherapy, potentially leading to more effective treatments for patients with various types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic redirection of T cells for cancer therapy. Westwood, JA., Kershaw, MH.[2010]

Adoptive transfer of antigen-specific T cells shows promise for treating viral infections in immunosuppressed patients, but achieving effective T-cell therapy for cancer is more challenging due to issues like T-cell tolerance and impaired survival in the body.

Genetic modification of T cells before transfer may help overcome obstacles such as tumor evasion tactics and improve the effectiveness of T-cell therapies for both cancer and infectious diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic modification of T cells for immunotherapy. Berger, C., Berger, M., Feng, J., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02869217

NCT02869217 | Study of TBI-1301 (NY-ESO-1 Specific ... The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with advanced solid ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10722137/

Safety and Efficacy of NY-ESO-1 Antigen-Specific T-Cell ... The Bayesian posterior probability that the ORR of TBI-1301 exceeded that of pazopanib for STS in the PALETTE study (i.e., 5.7%) was 100.0%. The ORR according ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)49697-X/pdf

Study of TBI-1301 (NY-ESO-1 specific TCR gene ... Pre-clinical murine studies demonstrated safety, persistence, and efficacy of transduced T cells. This study represents a Phase 1b study of TBI-1301 in patients ...

4. withpower.com withpower.com/trial/phase-1-sarcoma-synovial-8-2016-91d11

Genetically Modified T Cells for Solid Tumors This approach allows TCR-T cells to target both intracellular and cell-surface antigens, potentially making them more effective against solid tumors.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10972864/

Adoptive T cell therapy for solid tumors - PubMed Central - NIH In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0923753419593954

Adoptive T cell therapy with TBI-1301 results in gene ... Conclusions. ACT with TBI-1301 cells is safe and clinically active. Results provided here confirm long-term persistence of gene-engineered T cells with higher ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)59395-4/fulltext

Adoptive T cell therapy with TBI-1301 results in gene ... TBI-1301 was well tolerated, and there were no dose limiting toxicities. CRS grade 1-2 was experienced by 5 patients, with two patients requiring tocilizumab.