Study of PD-1Ab21-BCMA CAR-T Therapy for Consolidation of Multiple Myelomawith Renal Dysfunction

Renal dysfunction is a poor prognostic factor for multiple myeloma（MM）. Compared with MM patients with normal renal function, MM patients with renal dysfunction have significantly reduced median overall survival. The clinical outcomes of MM patients with improved renal function after treatment have shown some improvement, but are still inferior to those of MM patients with normal renal function. Although renal dysfunction is not an absolute contraindication for autologous hematopoietic stem cell transplantation, the therapeutic effect is unsatisfactory. For MM patients with renal insufficiency, the dosage of transplant pre-treatment drugs should be reduced according to creatinine clearance rate, and renal insufficiency increases the incidence of transplant related toxic side effects such as mucositis, infections, and other complications. In recent years, CART cell therapy has achieved good therapeutic effects in MM patients with renal dysfunction.Xuzhou Medical University Affiliated Hospital has reported 7 patients with refractory or recurrent MM accompanied by severe renal dysfunction. These patients were treated with CART cell therapy targeting BCMA or in combination targeting CD19/BCMA, with 5 cases achieving complete remission and 2 cases achieving partial remission. It is worth noting that the renal remission rate reached 100%. The results from Tongji Hospital in Wuhan show that CART can significantly improve renal function in relapsed and refractory MM patients. In multiple myeloma with renal dysfunction, BCMA CART cell consolidation therapy after first-line induction therapy may achieve rapid and lasting hematological and renal remission.

Numerous studies have confirmed that the anti-tumor effect of T cells depends on their proliferation ability. The therapeutic effect of PD-1 antibody depends on the recovery of CD8+T cell function with proliferative ability, while terminal failure CD8+T cells lacking proliferative ability do not respond to PD-1 antibody treatment. In clinical trials of T cell therapy for solid tumors, IL-2 should be administered simultaneously with T cell infusion to promote T cell proliferation. There are also many research reports on CAR-T cells expressing and secreting various cytokines both domestically and internationally. The T cell cytokine IL-2/15/21 is the most effective T cell response enhancer, but due to its numerous target cells, it has significant side effects. This greatly limits their clinical application. To this end, we have established an immunotherapy strategy that targets tumor specific T cells with cytokines. The developed anti-PD-1 antibody and IL-21 fusion protein (PD-1Ab21) not only exert the therapeutic effect of PD-1 antibody, but also target PD-1 positive tumor specific T cells in vivo with IL-21, promoting the formation of memory T cells and greatly improving the effectiveness of tumor treatment. Based on the above research, we developed BCMA CAR-T cells (PD-1Ab21-BCMA CAR-T) expressing PD-1 single chain antibody and IL-21 fusion protein (PD-1Ab21). The supernatant of CAR-T cell culture contains high-level PD-1Ab21 fusion protein that can bind to PD-1 on the cell surface, block anti-PD-1 signaling, and enrich IL-21 on the surface of CAR-T cells, binding to its receptor. In preclinical mouse tumor model experiments, it has been confirmed that the therapeutic effect of PD-1Ab21-BCMA CAR-T cells is significantly better than that of ordinary BCMA CAR-T cells. A clinical trial initiated by researchers for the treatment of refractory/recurrent MM was conducted at the First Medical Center of the General Hospital of the People's Liberation Army. Ten patients have been treated, with six achieving complete remission (CR), including one relapse and three VGPR, including three extramedullary lesions. There are also three cases yet to be evaluated, demonstrating good therapeutic efficacy and safety.

This study plans to explore the effectiveness and safety of PD-1Ab21-BCMA CAR-T cell immunotherapy as first-line consolidation therapy for multiple myeloma with renal dysfunction after first-line induction therapy, in order to improve the prognosis of such patients and provide new treatment options for first-line consolidation therapy of multiple myeloma with renal dysfunction.

Inclusion criteria

• Age: Over 14 years old
• Diagnosed with multiple myeloma accompanied by renal dysfunction, received ≥ 2 courses of clinical first-line treatment, evaluated efficacy above PR, and predicted survival of more than three months.
• The hospital examination meets the following indicators:

• ECOG physical status score 0-2 or KPS score>80 points
• Having sufficient venous access for single or intravenous blood collection, and no other blood cells Separation contraindications
• WBC≥1×109/L，LY≥0.3×109/L，
• ALT and AST ≤ 2.5 ULN
• Serum total bilirubin ≤ 2.0mg/dL (34.2 μmol/L)
• PT:INR<1.7 or PT prolonged by<4s compared to normal value

Exclusion criteria

• Pregnant or lactating women (the safety of this treatment for unborn babies is unknown, and the assessment of pregnancy status for female participants is negative in serum or urine pregnancy tests within 48 hours prior to infusion);
• Any uncontrollable active infection;
• Presence of active hepatitis B or C virus infection;
• HIV/AIDS infection;
• Has neurological disorders;
• Within 2 weeks prior to signing the informed consent form, systemic use of steroid drugs (inhalable steroids may be used);
• Allergies to immunotherapy and related drugs;
• Currently, there are patients with heart disease or poorly controlled hypertension who require treatment;
• Currently, patients with unstable or active ulcers or gastrointestinal bleeding;
• Patients with a history of organ transplantation or waiting for organ transplantation;
• Hyponatremia, blood sodium<125mmol/L;
• Baseline blood potassium<3.5mmol/L (potassium can be supplemented before participating in the study to restore blood potassium levels above this level);
• The patient needs anticoagulant therapy (such as warfarin or heparin);
• The patient requires long-term antiplatelet therapy (aspirin, dose>300mg/d); Clopidogrel, dose>75mg/d).

Additionally,

• Patients currently participating in other clinical trials;
• Researchers believe that other reasons are not suitable for clinical trial participants.