Tumor Neoantigen Vaccine SarVac Combined With Tumor Specific Lymphocyte Reinfusion in the Treatment of Advanced Sarcoma

A Prospective, Single-center, Double-arm, Phase I Clinical Trial of Tumor Neoantigen Vaccine SarVac Combined With Tumor-specific Lymphocyte Reinfusion in the Treatment of Patients With Advanced or Unresectable Sarcoma-based Solid Tumors Who Failed Standard Treatment.

The primary objective of this trial is to evaluate the safety and tolerability of the tumor neoantigen vaccine (SarcVac) in combination with a PD-1 antibody, with or without tumor-specific lymphocytes, in patients with advanced bone and soft tissue sarcoma who have failed first-line treatment. The secondary objectives are to assess the preliminary efficacy of SarcVac combined with a PD-1 antibody, with or without tumor-specific lymphocytes, in these patients and to evaluate whether the vaccine's efficacy demonstrates dose dependency.

Soft tissue sarcoma (STS) represents a heterogeneous group of malignant tumors. The prognosis is poor with an overall survival of 12-19 months for patients with metastasis. A critical unmet medical need is to develop novel and effective therapeutic approaches to improve the survival of patients with STS, for whom limited alternative chemotherapeutic or targeting regimens are available.

In recent years, tumor immunotherapy has emerged as a promising alternative to traditional treatments like surgery, chemotherapy, and radiotherapy. This approach includes four primary categories: immune checkpoint blockade, immunomodulators, adoptive cell transfer, and tumor vaccines. Immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4 antibodies, have shown efficacy in treating certain cancers. Tumor vaccines, which utilize tumor antigens to stimulate specific immune responses against cancer cells, offer notable advantages. These vaccines are characterized by low toxicity, high specificity, and the ability to induce immune memory, thereby reducing the risk of recurrence. Tumor-specific lymphocytes further enhance the immune system's capacity to target and kill tumor cells directly.

This study utilizes next-generation sequencing technology and bioinformatics analysis to accurately identify personalized tumor neoantigens. By screening for neoantigens with high MHC affinity and strong immunogenicity, we develop a personalized neoantigen vaccine, SarcVac. Subsequently, these neoantigens are used in vitro to activate and expand the patient's peripheral blood lymphocytes, yielding tumor-specific lymphocytes. This clinical trial will assess the safety and tolerability of the neoantigen vaccine (SarcVac) in combination with a PD-1 antibody, with or without tumor-specific lymphocytes, in patients with advanced solid tumors. Additionally, a preliminary assessment of its efficacy will be conducted.

Inclusion Criteria:

1. Before any procedures related to the research program, including screening and evaluation stage, signed informed consent.
2. Age≥18 years old, and≤70 years old ;
3. Pathologically diagnosed as solid tumors, including bone or soft tissue sarcoma, and staging for advanced or unresectable patients ;
4. Patients with first-line treatment failure ;
5. No previous tumor vaccine treatment ; no previous treatment with PD-1 antibody ;
6. According to the RECIST1.1 standard, there are measurable lesions and superficial lesions ;
7. The following three screening indicators should be met in the test screening period:

（1）The available tumor tissue samples ( paraffin sections and fresh surgical specimens ) were used for subsequent whole exome and transcriptome sequencing analysis and primary cell culture to obtain tumor neoantigen-related mutation sequence information and gene expression.

( 2 ) Available peripheral blood samples; ( 3 ) Tumor new antigen prediction analysis and in vitro laboratory testing; 8. ECOG score 0-1 ( see Appendix ) and expected survival time greater than 6 months ; 9. Patients were not allowed to use anti-tumor drugs and radiotherapy within 4 weeks before vaccination; 10. Patients with brain metastasis who were stable for at least one month after treatment can be included; 11. echocardiography showed left ventricular ejection fraction ≥ 50 %; 12. The results of laboratory tests should meet at least the following indicators :

1. White blood cell count ≥ 3.0 × 109 / L;
2. absolute neutrophil count ( ANC ) ≥ 1.5 × 109 / L ( without GCSF support ) ;
3. absolute lymphocyte count ( ALC ) ≥ 1.0 × 109 / L;
4. platelet ( PLT ) ≥ 75 × 109 / L;
5. hemoglobin ≥ 90g / dL ( no blood transfusion in the past 7 days ) ;
6. Prothrombin time or INR ≤ 1.5x normal upper limit time, unless receiving anticoagulant therapy;
7. partial thromboplastin time ( APTT ) ≤ 1.5x normal upper limit time, unless receiving anticoagulant therapy;
8. serum creatinine ≤ 1.5 × ULN ( upper limit of normal ) ; 24-hour creatinine clearance rate ≥ 60 mL / min;
9. Aspartate Aminotransferase (AST/SGOT) ≤ 2 × ULN;
10. Alanine Aminotransferase (ALT/SGPT) ≤ 2 × ULN;
11. total bilirubin ( TBIL ) ≤ 1 × ULN 13. Females with fertility were negative in pregnancy test before treatment ; consent must be given to the use of contraception or the prohibition of same-sex or opposite-sex sexual activity during treatment; 14. During the whole experiment, we can regularly go to the research institutions to carry out relevant testing, evaluation and management.

Exclusion Criteria:

• 1. Before any procedures related to the research program, including screening and evaluation stage, signed informed consent.

  2. Age≥18 years old, and≤70 years old ; 3. Pathologically diagnosed as solid tumors, including bone or soft tissue sarcoma, and staging for advanced or unresectable patients ; 4. Patients with first-line treatment failure ; 5. No previous tumor vaccine treatment ; no previous treatment with PD-1 antibody ; 6. According to the RECIST1.1 standard, there are measurable lesions and superficial lesions ; 7. The following three screening indicators should be met in the test screening period:

  （1）The available tumor tissue samples ( paraffin sections and fresh surgical specimens ) were used for subsequent whole exome and transcriptome sequencing analysis and primary cell culture to obtain tumor neoantigen-related mutation sequence information and gene expression.

( 2 ) Available peripheral blood samples; ( 3 ) Tumor new antigen prediction analysis and in vitro laboratory testing; 8. ECOG score 0-1 ( see Appendix ) and expected survival time greater than 6 months ; 9. Patients were not allowed to use anti-tumor drugs and radiotherapy within 4 weeks before vaccination; 10. Patients with brain metastasis who were stable for at least one month after treatment can be included; 11. echocardiography showed left ventricular ejection fraction ≥ 50 %; 12. The results of laboratory tests should meet at least the following indicators :

1. White blood cell count ≥ 3.0 × 109 / L;
2. absolute neutrophil count ( ANC ) ≥ 1.5 × 109 / L ( without GCSF support ) ;
3. absolute lymphocyte count ( ALC ) ≥ 1.0 × 109 / L;
4. platelet ( PLT ) ≥ 75 × 109 / L;
5. hemoglobin ≥ 90g / dL ( no blood transfusion in the past 7 days ) ;
6. Prothrombin time or INR ≤ 1.5x normal upper limit time, unless receiving anticoagulant therapy;
7. partial thromboplastin time ( APTT ) ≤ 1.5x normal upper limit time, unless receiving anticoagulant therapy;
8. serum creatinine ≤ 1.5 × ULN ( upper limit of normal ) ; 24-hour creatinine clearance rate ≥ 60 mL / min;
9. Aspartate Aminotransferase (AST/SGOT) ≤ 2 × ULN;
10. Alanine Aminotransferase (ALT/SGPT) ≤ 2 × ULN;
11. total bilirubin ( TBIL ) ≤ 1 × ULN 13. Females with fertility were negative in pregnancy test before treatment ; consent must be given to the use of contraception or the prohibition of same-sex or opposite-sex sexual activity during treatment; 14. During the whole experiment, we can regularly go to the research institutions to carry out relevant testing, evaluation and management.