Engineered T-Cell Therapy for Cancer

Recruiting at 8 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants, Aminoglycosides

Disqualifiers: CNS malignancy, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

162 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop any systemic therapy at least 2 weeks or 3 half-lives (whichever is shorter) before enrolling. This means you may need to stop certain medications before participating.

What data supports the effectiveness of the treatment NT-175 for cancer?

Research shows that engineered T cells, like those used in NT-175, have shown promise in targeting and killing cancer cells. Studies have demonstrated that these T cells can be modified to specifically attack cancer cells, leading to tumor regression in some patients. ^{1 2 3 4 5}

Is engineered T-cell therapy generally safe for humans?

Engineered T-cell therapies, like CAR T cells and TCR T cells, have shown promise in treating certain cancers, but they can also cause side effects such as cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Clinical trials have identified these safety concerns, and ongoing research aims to balance effective cancer targeting with minimizing harm to normal tissues. ^{2 6 7 8 9}

What makes the NT-175 treatment unique for cancer?

NT-175 is unique because it involves engineered T cells that are genetically modified to specifically target and kill cancer cells, potentially offering a more precise and effective treatment compared to traditional therapies. This approach can also help the immune system remember and continue fighting cancer over time. ^{1 10 11 12 13}

What is the purpose of this trial?

This trial tests NT-175, a personalized treatment made from a patient's own immune cells, in patients with advanced cancers that have a specific genetic mutation. The treatment works by enhancing the immune system to attack cancer cells.

Research Team

AstraZeneca

Principal Investigator

AstraZeneca

Eligibility Criteria

Adults over 18 with advanced solid tumors positive for HLA-A*02:01 and TP53 R175H mutation, who've tried standard treatments without cure. Eligible cancers include NSCLC, colorectal adenocarcinoma, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, breast cancer or other solid tumors. Must have measurable disease and be in good physical condition.

Inclusion Criteria

I have been diagnosed with a specific type of cancer, such as lung, colon, head and neck, pancreatic, breast, or another solid tumor.

I am able to understand and sign the consent form.

Subject has at least 1 measurable lesion per computed tomography (CT) scan or magnetic resonance imaging (MRI)

Exclusion Criteria

I have not had serious heart problems or heart failure in the last 6 months.

I have Li-Fraumeni syndrome or a relative diagnosed with it.

I haven't had any systemic therapy for at least 2 weeks or 3 half-lives, whichever is shorter.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Investigate escalating doses of NT-175 to evaluate safety and determine the maximum tolerated dose (MTD)

Up to 24 months

Disease Histology Evaluation

Evaluate safety and preliminary anti-tumor activity at or below the MTD in specific disease histologies

Up to 24 months

Disease Cohort Expansion

Further evaluate the preliminary anti-tumor activity and safety of NT-175 at the recommended phase 2 dose (RP2D) in disease-specific settings

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 24 months

Treatment Details

Interventions

• NT-175

Trial Overview The trial is testing NT-175 T cells engineered to target the TP53 R175H mutation in various advanced solid tumors. It's a Phase I study assessing safety and how well these modified T cells work against the cancer.

Participant Groups

Group I: Part 2: Disease Cohort Expansion Experimental Treatment 1 Intervention

TCR T Cell Product at the RP2D

Group II: Part 1: Disease Histology Evaluation Experimental Treatment 1 Intervention

TCR T Cell Product at the MTD

Group III: Dose Escalation and Expansion Experimental Treatment 1 Intervention

Dose Escalation of TCR T cell product

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Neogene Therapeutics, Inc.

Lead Sponsor

Trials

2

Recruited

190+

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]

Engineered T-cells targeting the NY-ESO-1 cancer-testis antigen showed increased activation and cytotoxicity against NY-ESO-1-positive tumor cells, indicating their potential effectiveness in treating solid tumors.

The study demonstrated that these modified T-cells not only proliferated and activated in response to the tumor cells but also produced key cytokines associated with cancer cell killing, suggesting a strong mechanism of action for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-Engineered Lymphocytes Targeting NY-ESO-1: In Vitro Assessment of Cytotoxicity against Tumors. Alsalloum, A., Alrhmoun, S., Shevchenko, J., et al.[2023]

A phase 1 clinical trial of T cell therapy targeting HPV-16 E7 showed promising results, with 6 out of 12 patients experiencing significant tumor regression, including 4 patients who had previously not responded to anti-PD-1 treatment.

The study indicates that engineered T cells can effectively target and reduce tumors in epithelial cancers, but also highlights challenges such as resistance mechanisms that may limit the effectiveness of this therapy in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nagarsheth, NB., Norberg, SM., Sinkoe, AL., et al.[2023]

In a study involving 16 healthy donors, researchers found that using specific activation conditions (soluble anti-CD3/CD28 mAbs with IL15 and IL21) improved the quality and function of gene-modified T cells, which is crucial for effective cancer treatment.

These optimized T cells showed better binding to target molecules and a more favorable phenotype, suggesting that these methods could enhance the efficacy of CAR and TCR therapies in future clinical trials for patients with certain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. Lamers, CH., van Steenbergen-Langeveld, S., van Brakel, M., et al.[2018]

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]

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]

Adoptive cellular therapy, particularly using tumor-infiltrating lymphocytes (TILs), shows significant promise in treating cancers like melanoma, indicating a need for further development in clinical settings.

Genetically engineered T cells can enhance antitumor activity, but there are risks of toxicity when these cells target normal tissues, highlighting the need for careful balance in future therapies and clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of adoptive cell therapy for cancer: a clinical perspective. Hawkins, RE., Gilham, DE., Debets, R., et al.[2021]

A systematic review of 109 papers identified only 11 studies that utilized patient-reported outcomes (PROs) in adoptive cell therapy (ACT) for cancer, highlighting a lack of ACT-specific PRO measures.

The most commonly used PROs were the PROMIS-29 and EQ-5D, but there is a need for more tailored instruments and research on optimal timing for PRO assessments to better capture patient experiences during and after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcome (PRO) instruments used in patients undergoing adoptive cell therapy (ACT) for the treatment of cancer: a systematic review. Taylor, S., Law, K., Coomber-Moore, J., et al.[2023]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

Recent advancements in delivering transgenes to human T cells have improved the effectiveness of T cell therapies for cancer, allowing for the creation of T cells that can specifically target tumors.

While genetically modified T cells have shown success in clinical trials, they can also cause significant on-target toxicity, highlighting the need for careful selection of target antigens and strategies to manage potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered T cells for anti-cancer therapy. Turtle, CJ., Hudecek, M., Jensen, MC., et al.[2021]

Gene-engineered T-cell therapies are expected to significantly improve cancer treatment over the next decade by specifically targeting and destroying cancer cells.

These therapies leverage advancements in immunology and bioengineering to create T cells that not only attack metastatic lesions but also provide lasting immunity against cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T Cells as the Future of Cancer Therapy. Ribas, A.[2022]

Adoptively transferred T cells can effectively target and kill tumor cells by migrating to distant sites and infiltrating fibrotic tissue, showcasing their potential in cancer therapy.

Recent advancements in genetic engineering of T cells aim to enhance their specificity, potency, and safety, which could lead to improved clinical outcomes in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered T cells for cancer treatment. Anurathapan, U., Leen, AM., Brenner, MK., et al.[2021]

A new method for purifying engineered immune cells has been developed, which is ready for Good Manufacturing Practice (GMP) and could enhance the effectiveness of T cell therapy in cancer treatment.

By removing less effective T cell subsets and poorly engineered cells, this purification technique aims to improve the overall success rates of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The next step toward GMP-grade production of engineered immune cells. Kierkels, GJ., Straetemans, T., de Witte, MA., et al.[2021]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

TCR-Engineered Lymphocytes Targeting NY-ESO-1: In Vitro Assessment of Cytotoxicity against Tumors. [2023]

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

TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. [2023]

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

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. [2018]

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

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

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

Development of adoptive cell therapy for cancer: a clinical perspective. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Patient-reported outcome (PRO) instruments used in patients undergoing adoptive cell therapy (ACT) for the treatment of cancer: a systematic review. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. [2022]

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

Engineered T cells for anti-cancer therapy. [2021]

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

T Cells as the Future of Cancer Therapy. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Engineered T cells for cancer treatment. [2021]

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

The next step toward GMP-grade production of engineered immune cells. [2021]