Combination of Toripalimab and JS004 Therapy for ccRCC

Inclusion Criteria:

1. The patient voluntarily participated in this study, signed an informed consent form,and showed good compliance;

2. Age ≥ 18 years old;

3. Local recurrence or metastatic renal cell carcinoma that has undergone curativesurgical resection and has been histologically confirmed;

4. Previous treatment history of the subject: patients who have received one type ofsystemic therapy in the past and have progressed or become intolerant, as well aspatients who have progressed within 6 months after previous adjuvant or neoadjuvanttherapy;

5. Patients are required to provide postoperative tissue wax blocks for research andtesting purposes, which should include both renal cancer tissue and normal kidneytissue adjacent to the cancer. Alternatively, at least 20 slices of previoussurgical specimens should be provided for HE/IHC/spatial omics testing; The criteriafor detecting TLS positivity are: detecting at least one CD3+/CD20+lymphocyteaggregate containing>700 cells in the tumor;

6. Have at least one measurable lesion (RECIST 1.1);

7. ECOG score 0-1;

8. The main organ functions well, and the laboratory examination indicators meet thefollowing criteria:

(1) Blood routine examination:

• Hemoglobin (HB) ≥ 80g/L;

② Absolute neutrophil count (ANC) ≥ 1.5 × 109/L; Total white blood cell count ≥ 3.5 × 109/L;

③ Platelet count (PLT) ≥ 80 × 109/L; (2) Blood biochemistry test:

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for liver/bone metastases; ≤ 5 ULN for tumor bone metastases);

• Serum total bilirubin (TBIL) ≤ 1.5 × ULN; ③ Serum creatinine Cr ≤ 1.5 × ULN orcreatinine clearance rate ≥ 60 ml/min; (3) Coagulation function test: Activatedpartial thromboplastin time (APTT), international normalized ratio (INR),prothrombin time (PT) ≤ 1.5 × ULN; (4) Thyroid function: Thyroid stimulatinghormone (TSH) ≤ 1 × ULN (if abnormal, FT3 and FT4 levels should be examinedsimultaneously. If FT3 and FT4 levels are normal, they can be included in thegroup) 9. Women of childbearing age must confirm their non pregnancy statusbefore enrollment, and all enrolled subjects (male or female) should takeadequate contraceptive measures throughout the entire treatment period andwithin 4 weeks after the end of treatment; 10. The patient voluntarily joinedthis study, signed an informed consent form, had good compliance, and was ableto accept follow-up from the trial personnel.

Exclusion Criteria:

Patients with any of the following conditions are not eligible for inclusion in this study:

1. Known to have allergic reactions to the therapeutic drugs and/or any excipients usedin this study;

2. Four weeks before the first study medication, receive systemic treatment with otheranti-tumor drugs (if it has a half-life of five, it can be included in the group),or receive local anti-tumor treatment, or receive clinical investigational drug ordevice treatment;

3. Patients who have previously received treatment with anti BTLA or anti HVEMantibodies;

4. Subjects with standard second-line treatment and/or contraindications to the use oftrastuzumab or JS004;

5. Subjects with previous or concurrent malignant tumors (excluding cured cervicalcancer, basal or squamous skin cancer);

6. Active autoimmune diseases that require systemic treatment within the past 3 months,or clinically severe autoimmune disease records, or syndromes that require systemicsteroids or immunosuppressants;

7. Known history of human immunodeficiency virus infection (HIV1/2 antibody positive);

8. Female participants who are pregnant, breastfeeding, or planning to become pregnantduring the study period;

9. Patients with bleeding tendencies (such as active gastrointestinal ulcers) ortreated with anticoagulants or vitamin K antagonists such as warfarin, heparin, ortheir analogues;

10. History of interstitial lung disease, drug-induced interstitial lung disease,radiation pneumonitis, symptomatic interstitial lung disease, or any evidence ofactive pneumonia detected on chest CT scan within 4 weeks prior to the first studydrug treatment;

11. According to the researcher's judgment, there are accompanying diseases that pose aserious threat to patient safety or affect the completion of the study.

12. There are other serious physical or mental illnesses or laboratory abnormalitiesthat may increase the risk of participating in the study, or interfere with thestudy results, as well as patients who the researcher deems unsuitable toparticipate in this study.