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

22 Participants Needed

Trial Summary

What is the purpose of this trial?

The target populations for this phase I study with TBI-1301 are patients with advanced solid tumors. Patients' tumors will be required to express NY-ESO-1, which include but is not limited to ovarian cancer, synovial sarcoma, esophageal cancer, lung cancer, bladder cancer, liver cancer, and malignant melanoma. Patients must be positive for HLA-A\*02:01 or HLA-A\*02:06 and the patient's tumor tissue must be positive for NY-ESO-1 antigen expression. The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. The manufacturing of T cells takes about 1 month to complete. The T cells will be given back to the subject through an intravenous infusion. 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 tumors. The purpose of this study is to evaluate the safety profile of TBI-1301, to determine the recommended phase 2 (RP2D) dose of TBI-1301 when administered following cyclophosphamide and fludarabine pre-treatment, to evaluate the safety of repeat dosing of TBI-1301, to assess the presence/absence of RCR appearance after TBI-1301 infusion, to assess the presence or absence of clonality by LAM-PCR, and to evaluate evidence of efficacy of TBI-1301 using RECIST v1.1.

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.

What data supports the effectiveness of the treatment TBI-1301 for solid tumors?

Research shows that genetically modified T cells, like those used in TBI-1301, have shown promise in targeting and killing cancer cells in solid tumors. These engineered T cells can be designed to recognize specific markers on cancer cells, leading to potent anti-tumor effects, as demonstrated in various studies and clinical trials. ^{1 2 3 4 5}

What safety data exists for genetically modified T cells in humans?

Genetically modified T cells, like CAR T cells, have shown potential in treating cancers but can cause side effects such as cytokine release syndrome (a severe immune reaction), neurologic issues, and allergic reactions. Efforts are being made to manage these risks, and some trials have included safety features like a 'suicide switch' to remove the cells if needed. ^{6 7 8 9 10}

How is the treatment TBI-1301 different from other treatments for solid tumors?

TBI-1301 is unique because it involves genetically modified T cells with T cell receptors (TCR-T cells) that can recognize a wider range of tumor antigens compared to traditional CAR-T cell therapies, which are limited in treating solid tumors. This approach allows TCR-T cells to target both intracellular and cell-surface antigens, potentially making them more effective against solid tumors. ^{1 5 11 12 13}

Eligibility Criteria

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

Platelets ≥ 75x10^9/L (75,000/μl)

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

AST(SGOT), ALT(SGPT) < 3.0 x ULN (< 5 x ULN with known liver metastases)

Exclusion Criteria

Pregnant women are excluded.

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

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

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

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

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

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. [2023]

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

Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Genetic redirection of T cells for cancer therapy. [2010]

6. Ireland pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. [2020]

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

Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. [2021]

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

Toxicity and management in CAR T-cell therapy. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Challenges in T cell receptor gene therapy. [2023]

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

Engineering hematopoietic stem cells to create melanoma specific CTL. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Cancer immunotherapy with lymphocytes genetically engineered with T cell receptors for solid cancers. [2020]

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

Adoptive antitumor immunotherapy in vitro and in vivo using genetically activated erbB2-specific T cells. [2017]

13. England pubmed.ncbi.nlm.nih.gov

Genetic modification of T cells for immunotherapy. [2019]