CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Subjects fully understand the trial purpose, study design, procedures, and potential adverse reactions, voluntarily agree to participate, and sign written informed consent before any study-related procedures are performed.
2. Subjects have no contraindications to leukapheresis.
3. Subjects are aged ≥ 18 years at screening.
4. Subjects have a confirmed diagnosis of relapsed or refractory multiple myeloma (RRMM) consistent with the International Myeloma Working Group (IMWG) diagnostic criteria.
5. Subjects have documented disease progression after receiving at least two lines of prior systemic therapy. Autologous or allogeneic hematopoietic stem cell transplantation (SCT) with corresponding supportive care is defined as one line of therapy. Subjects must have progressed after at least one proteasome inhibitor and one immunomodulatory agent. Subjects must have previously received CD38 monoclonal antibody therapy or be unsuitable for CD38 monoclonal antibody administration. All subjects must be currently ineligible for or decline autologous or allogeneic SCT.
6. Subjects have evaluable disease and meet at least one of the following conditions:

   1. Serum M-protein ≥ 10 g/L; for subjects with IgA, IgD, IgE, or IgM multiple myeloma, serum M-protein ≥ 5 g/L.
   2. 24-hour urinary M-protein ≥ 200 mg.
   3. For light-chain multiple myeloma without measurable serum or urine M-protein: abnormal serum κ/λ free light chain (FLC) ratio and involved FLC ≥ 100 mg/L;
   4. Presence of evaluable plasmacytoma on imaging examination, or bone marrow plasma cell proportion ≥ 10%, with reserved bone marrow fluid or tissue for CS1 expression detection.
7. Subjects have adequate organ function within the screening period and within 10 days prior to treatment initiation, as defined below:

   a. Renal function: i. Serum creatinine ≤ 2.5 × upper limit of normal (ULN); OR ii. 24-hour creatinine clearance ≥ 30 mL/min (calculated via the Cockcroft-Gault formula).

   b. Hepatic function: i. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN; ii. Total bilirubin (TBil) ≤ 2.0 × ULN. c. Hematological function: i. Absolute neutrophil count ≥ 0.5 × 109/L; ii. Absolute lymphocyte count ≥ 0.7 × 109/L; iii. Platelet count ≥ 25 × 109/L; iv. Hemoglobin ≥ 60 g/L. d. Biochemical and other baseline indicators: i. Corrected serum calcium ≤ 14 mg/dL (≤ 3.5 mmol/L) or ionized calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L); ii. Prothrombin time (PT) ≤ ULN + 3 seconds; iii. Oxygen saturation ≥ 92% while breathing ambient air.
8. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to treatment initiation. Post-menopausal status (minimum 2 years of amenorrhea), prior total hysterectomy, bilateral tubal ligation, bilateral oophorectomy, or congenital infertility confirms non-childbearing potential.
9. Subjects of childbearing potential, and male subjects with sexually active female partners of childbearing potential, must agree to use highly effective contraceptive methods (failure rate \< 1%) throughout the treatment period and for 12 months after the last study drug administration, including tubal ligation, male sterilization, hormonal implants, combined oral/injectable hormonal contraceptives, and approved intrauterine devices.

Exclusion Criteria:

1. Female subjects who are pregnant or breastfeeding.
2. Subjects unable to tolerate venous puncture required for leukapheresis and screening laboratory assessments.
3. Subjects with any of the following prior treatment histories:

   1. Prior hematopoietic stem cell transplantation within 12 weeks before leukapheresis.
   2. Administration of any live vaccine within 4 weeks before leukapheresis or planned live vaccine administration during study participation.
   3. Use of immunosuppressive agents for the prophylaxis or treatment of graft-versus-host disease (GVHD) within 4 weeks before leukapheresis, or a confirmed diagnosis of acute or chronic GVHD at screening.
   4. Receipt of any investigational product within 4 weeks prior to signing the informed consent form.
   5. Concurrent enrollment in any other interventional clinical trial at screening.
4. Subjects presenting with any of the following medical conditions at screening:

   1. Confirmed active central nervous system involvement, or clinical manifestations suggestive of multiple myeloma meningeal infiltration.
   2. Poorly controlled hypertension despite stable medical therapy, defined as systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg at screening.
   3. Left ventricular ejection fraction (LVEF) \<50% measured via screening Doppler echocardiography.
   4. Any arrhythmia graded Grade 2 or higher per NCI CTCAE Version 5.0.
   5. Prolonged QTc interval corrected by Fridericia formula (QTcF), defined as QTcF \>450 ms in male subjects or QTcF \>470 ms in female subjects. The correction formula is QTcF = QT / RR0.33. Subjects with such QTcF prolongation and concomitant use of QT-prolonging medications (including Class Ia and Class III antiarrhythmic agents) are excluded.
   6. Documented personal history of torsades de pointes or congenital long QT syndrome.
   7. Occurrence of any of the following cardiovascular adverse events within 6 months prior to signing informed consent:

   i. Myocardial infarction; ii. Severe or unstable angina pectoris; iii. Coronary artery bypass graft or peripheral arterial bypass surgery; iv. Congestive heart failure. h. Medical history of severe craniocerebral trauma, altered mental status, epilepsy, severe cerebral ischemia, or intracerebral hemorrhage.

   i. Any congenital or acquired neurological, vascular, or systemic disorder that may interfere with study safety monitoring or efficacy evaluation (examples include Parkinson's disease, cerebral palsy, diabetic neuropathy).

   j. Uncontrolled active infectious disease identified by investigator assessment during screening.

   k. Confirmed human immunodeficiency virus (HIV) infection. l. Positive hepatitis B surface antigen (HBsAg) and positive hepatitis B core antibody with active hepatitis B viremia (HBV DNA level exceeding the upper limit of normal).

   m. Positive anti-hepatitis C virus antibody (Anti-HCV) with detectable active HCV viremia, defined as HCV RNA ≥ 1.00×102 copies/mL.

   n. Well-documented severe hypersensitivity or anaphylactic reaction to human, humanized, or murine monoclonal antibodies.

   o. Prior history of solid organ transplantation. p. History of alcohol or illicit drug abuse within 52 weeks before screening visit, or ongoing alcohol abuse judged by the investigator.

   q. Unremitted psychotropic substance abuse history or clinically significant psychiatric disorders.

   r. Severe, inadequately controlled concomitant diseases (including but not limited to neurological, renal, hepatic, endocrine, and gastrointestinal disorders) that would prevent safe study participation per investigator judgment.

   s. Any clinically significant abnormal findings across nervous, cardiovascular, hematologic/lymphatic, immune, renal, hepatic, gastrointestinal, respiratory, metabolic, or skeletal systems that warrant exclusion from study enrollment.
5. Any other clinical condition determined by the investigator to render the subject unsuitable for participation in this trial.

主要终点：Number of Participants With Dose-Limiting Toxicities (DLTs) Within 28 Days After Autologous CS1 CAR-T Cell Infusion · DLT is defined as a treatment-related adverse event or laboratory abnormality occurring after CS1 CAR-T cell infusion that meets protocol-defined criteria and is not attributable to the underlying disease, disease progression, concomitant disease, or concomitant medication. Hematologic DLT is non-disease-related Grade 4 toxicity lasting more than 30 days, excluding lymphopenia. Non-hematologic DLT is treatment-related Grade ≥3 toxicity that does not decrease to Grade ≤1 or baseline within 14 days despite appropriate management. Protocol-specified exceptions apply. The number and percentage of participants with DLTs will be summarized by CS1 CAR-T cell dose level. · From the first CS1 CAR-T cell infusion through Day 28 after the first infusion；Number of Participants With Treatment-Related Adverse Events Within 28 Days After Autologous CS1 CAR-T Cell Infusion · Treatment-related adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE). The number and percentage of participants experiencing treatment-related adverse events will be summarized by severity grade and relationship to CS1 CAR-T cell infusion during the protocol-defined 28-day DLT assessment period. · From the first CS1 CAR-T cell infusion through Day 28 after infusion
次要终点：Objective Response Rate (ORR) According to the International Myeloma Working Group (IMWG) 2016 Criteria；Complete Response Rate (sCR + CR) According to the International Myeloma Working Group (IMWG) 2016 Criteria；Time to Response (TTR) According to the International Myeloma Working Group (IMWG) 2016 Criteria；Duration of Response (DOR) According to the International Myeloma Working Group (IMWG) 2016 Criteria；Progression-Free Survival (PFS) After CS1 CAR-T Cell Infusion；Overall Survival (OS) After CS1 CAR-T Cell Infusion；Disease Control Rate (DCR) According to the International Myeloma Working Group (IMWG) 2016 Criteria

• CS1 CAR-T cell infusion · EXPERIMENTAL · Patients with relapsed/refractory multiple myeloma will receive CS1 CAR-T cell therapy as monotherapy via intravenous infusion in this dose-escalation trial. Three dose cohorts will be evaluated: 1.0 × 10⁶/kg, 2.5 × 10⁶/kg, and 5.0 × 10⁶/kg CS1 CAR-positive T cells.

This investigator-initiated, exploratory clinical trial is designed to evaluate the feasibility, safety, and preliminary antitumor activity of autologous CS1-targeted chimeric antigen receptor T (CAR-T) cells in adults with relapsed or refractory multiple myeloma (MM). Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of plasma cells. Despite advances in treatment, patients with relapsed or refractory disease often have limited therapeutic options after multiple lines of therapy. CS1, also known as signaling lymphocytic activation molecule family member 7 (SLAMF7; CD319), is highly expressed on myeloma cells throughout the course of disease and has been investigated as a therapeutic target. The clinical activity of the anti-SLAMF7 monoclonal antibody elotuzumab supports the rationale for targeting this antigen. CS1-targeted CAR-T cell therapy is being investigated as a potential treatment option for patients with relapsed or refractory multiple myeloma. This is an open-label, single-center, non-randomized, Phase I dose-escalation study evaluating autologous CS1-targeted CAR-T cells. The primary objectives are to evaluate the feasibility and safety of autologous CS1-targeted CAR-T cell therapy and to assess its preliminary antitumor activity. Eligible participants are adults with relapsed or refractory multiple myeloma diagnosed according to the International Myeloma Working Group (IMWG) criteria who have received multiple prior lines of therapy, have measurable disease, and meet protocol-defined organ function requirements.