KRAS-Specific Autologous TCR-T Cell Therapy for KRAS Mutation in Advanced Solid Tumors

This is a single-center, open-label, single-arm, dose-escalation study aimed at evaluating the safety and preliminary efficacy of KRAS-specific autologous TCR-T cells in patients with advanced solid tumors harboring KRAS mutations (e.g., G12V).

T cell receptor-gene engineered T cells (TCR-T) therapy is a highly targeted form of cellular immunotherapy. It is safer than Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) and is currently a hot topic in immunotherapy. In the case of advanced pancreatic cancer with KRAS mutations, the infusion of TCR-T cells has achieved good efficacy and safety, further suggesting the promising prospects of TCR-T cell immunotherapy for advanced solid tumors with KRAS gene mutations.

It is planned to enroll 9 - 18 patients with advanced solid tumors who have KRAS mutations, HLA-A\*11:01 genotype, and have failed standard treatments. A single-center, open-label, single-arm study design will be adopted. The KRAS-specific autologous TCR-T cell injection will be used to treat these patients. The primary endpoint is safety, and the secondary endpoints include efficacy, cell activity, etc. It is planned to select three dose groups with 5×10⁹, 1×10¹⁰, and 2×10¹⁰ TCR-T cells respectively, and conduct dose escalation using a 3 + 3 study design.

The key steps involved in the study are the preparation and quality control of TCR-T cells, lymphocyte depletion (lymphodepletion), and the infusion of autologous TCR-T cell injection. Record and promptly handle specific adverse reactions of cellular immunotherapy, such as cytokine release syndrome (CRS), various other adverse events, off-target effects of TCR-T, and adverse events related to tumorigenic potential, etc., to obtain safety data. It is hoped that the results of this study will bring a new future for patients with advanced solid tumors with specific KRAS mutations.

Eligibility Criteria:
Inclusion Criteria:

* Patients aged 18-70 years.
* Histologically or cytologically confirmed advanced solid tumors (e.g., colorectal cancer, pancreatic cancer, NSCLC) with KRAS G12V mutations and HLA-A\*11:01 genotype.
* Failed standard therapies or no effective treatment available.
* ECOG performance status of 0-1.
* Life expectancy of ≥3 months.
* Presence of at least one measurable lesion as defined by RECIST 1.1 criteria.
* Female patients of childbearing potential must agree to use highly effective contraceptive methods during the study and for at least 6 months after the last dose. A negative pregnancy test within 7 days prior to treatment initiation is required.
* Written informed consent provided by the patient, with an expectation of compliance with study procedures.

Exclusion Criteria:

* 1.Prior treatment with gene-modified T-cell therapies.
* Current treatment with T-cell suppressive agents (e.g., cyclophosphamide, FK506, tripterygium glycosides) or T-cell stimulants.
* Chemotherapy, targeted therapy, immunotherapy, or investigational drugs administered within 2 weeks, or radiotherapy within 4 weeks prior to enrollment.
* Significant organ dysfunction, as evidenced by:

  * leukocytes\<3.0 x 109/L
  * absolute neutrophil count \>1.5 x 109/L
  * hemoglobin\<90g/L
  * platelets \<100 x 109/L
  * Creatinine\>1.5×ULN or creatinine clearance \<50mL/min
  * lymphocytes\<0.5 x 109/L
  * total bilirubin\>3×ULN; ALT/AST\>3×ULN (or \>5× ULN in patients with liver metastases)
  * INR/APTT\>1.5×ULN；
  * SpO2≤93%
* Presence of serious diseases and comorbidities, including but not limited to: severe heart disease, cerebrovascular disease, seizures, poorly controlled diabetes (such as Type 1 diabetes or insulin-dependent diabetes), pancreatic dysfunction, severe infections, active gastrointestinal ulcers, gastrointestinal bleeding, mechanical or paralytic bowel obstruction, pulmonary fibrosis, renal failure, respiratory failure, etc.
* History of severe cardiovascular diseases within the past 6 months, including but not limited to: myocardial infarction, severe or unstable angina, coronary artery or peripheral artery bypass surgery, New York Heart Association (NYHA) Class III or IV heart failure, etc.
* Left ventricular ejection fraction (LVEF) \< 50%.
* Symptomatic brain metastases unless stabilized with prior treatment (e.g., surgery or radiotherapy).
* Known history of myelodysplastic syndrome, lymphoma, or other malignancies.
* Known allergy to albumin, investigational drugs, or their excipients.
* Active autoimmune diseases, including but not limited to acquired/congenital immunodeficiency, organ transplantation, autoimmune hepatitis, systemic lupus erythematosus, or inflammatory bowel disease.
* Active hepatitis B, hepatitis C, or HIV infection.
* Pregnancy or breastfeeding.
* Uncontrolled mental or neurological disorders.
* Any condition deemed unsuitable for study participation by the investigator.