Immune Combination Therapy with NK Cell and Pembrolizumab Showed Therapeutic Efficacy in Treating Advanced Solid Tumors

Tumor size in the lungs before/after therapy



This study, conducted a two-phase study treating advanced solid patients with NK cell therapy (phase 1) or NK and anti-PD-1 inhibitor, pembrolizumab (phase 2).The results in our study indicated that immune combination therapy with NK cell and pembrolizumab might be a promising and safe approaches to treating advanced solid tumors.

Patients characteristics

14 patients with advanced cancer (5 breast cancer, 3 NSCLC, 2 colorectal cancer, 1 ovarian cancer, 1 esophageal cancer, 1 soft tissue sarcoma, 1 pancreatic cancer) who were resistant to standard therapy, with the median age of these patients was 55 (ranging from 45 to 82) years old. Previously, all these patients had received several cycles of standard therapies, including surgical resection, traditional chemotherapy, radiotherapy and immune therapy. All patient has a Karnofsky performance status (KPS)>60 and adequate organ function.


Generation of NK cells
Human PBMCs were cultured in a medium which was coated by NK cell activating cytokines. IL-2 and self-serum were added into this medium. About 14-18 days were needed to obtain enough NK cells for clinical infusion.


In the first phase of this study, 9 patients received NK cell therapy, and all of them completed at least 2 courses of infusion (4 completed a full cycle of infusion, 2 received multi-cycle infusions, 3 patients received 2 or 3 courses of infusion). The median dose of NK cells was 10.6×109 cells.
In the second phase, 5 patients received NK cell and Keytruda therapy. Among them, 3 patients (P10, P11 and P12) received 2 cycles of infusions and 2 patients (P13 and P14) received 2 courses of infusion. The median dose of NK cells was 10.9×109 cells. The Keytruda was administrated at 200 mg each course for adult patients.


In the NK cell group, all fusions of NK cells were well tolerated by all patients. The mild fever was the
most common adverse event observed in this group, and only one patient (P8) experienced high fever (>39°C). All symptoms were quickly relieved after conventional treatments.
In the NK cell and Keytruda group, the degree of adverse events was relatively more serious than that in NK cell group. 4 patients (P10, P11, P12 and P14) experienced mild to moderate fever and chills after infusion, especially after Keytruda administration. Besides, mild local erythroderma (grade 1) was observed after Keytruda administration in P11 and P12, which was relieved after symptomatic treatments and did not have a negative effect on the overall treatment schedule in this study. No obvious adverse event was observed in P13.
Clinical outcome
In the first phase, 3 of 9 patients achieved a stable disease (SD) 4 weeks after NK cell therapy; 5 patients experienced progressive disease (PD) after treatment; 1 patient (P4) was response non-evaluable (NE) as he refused to accept the second course of infusion and withdraw from the study. Among the 3 patients who achieved SD after treatment, P2 was a 64-year-old man with a diagnosis of esophageal cancer accompanying lymph nodes and left pleura metastasis. After infusion of 2 courses of NK cells, the tumor remained the primary size for 4 weeks detected by CT and ultrasound test. Besides, the tumor makers (CA- 199 and CA-242) had a significant decrease after treatment. Especially, the CA-242 evidently decreased from over 200 KU/L to 143 KU/L 4 weeks after infusion.
For patient 7 who was diagnosed as soft tissue sarcoma with lung and colon metastasis, a stable disease was achieved after treatment. The lung metastasis remained the primary size 4 weeks after NK cells infusion. For 2 patients (P8 and P9) (breast cancer) with advanced breast cancer, 3 and 2 cycles of infusion were conducted in them respectively. For patient 8, she had a stable disease after each cycle of infusion, and this SD remained for about 8 weeks after treatment. However, for patient 9, the disease had a significant progression after 2 cycles of infusion, and the patient finally died of it.
In the second stage of this study, 5 patients received NK cell and Keytruda therapy, and 1 of them (P12 with NSCLC) achieved partial remission (PR), 4 patients (P10, P11, P13 and P14) (rectal, NSCLC, pancreatic, colon) achieved SD after treatment. For patient 10, she had received anti-CEA chimeric antigen receptor (CAR)-T cell therapy for refractory/relapsed rectal cancer 4 months ago, and a stable disease was achieved after CAR-T. However, the disease had a progression 2 months after CAR-T therapy and this patient turned to this study accepting NK and Keytruda treatment. After 2 cycles of treatment, her tumor remained stable, the metastasis in the lung was no longer progressed. Patient 11 was diagnosed as NSCLC with lymph nodes and spine metastasis, receiving 2 cycles of NK and Keytruda treatment. The metastasis in the spine was no longer progressed and remained stable for 4 months after treatment.
For patient 12, he was diagnosed as NSCLC with metastases in the lymph nodes, bone and brain, and accepted anti-CEA CAR-T cell therapy 5 months before this study. After CAR-T, his disease remained stable for about 3 months but rapidly progressed afterwards. In this study, he accepted 2 cycles of NK and Keytruda treatment. Surprisingly, levels of the tumor markers including CA-125, CA-199, CA-242 and CEA had an evident decrease after 2 cycles of infusion. Besides, the primary lesions in the lungs showed apparent attenuation and almost disappeared after treatment.


These primarily showed that NK cell and anti-PD-1 combination therapy could be a promising and safe approach to treating patients with advanced solid tumors, and it is worth expanding the sample sizes to further verify the efficacy and safety of this therapy.

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Scientific article publishing date 12/14/2021

Immucura identifier BSC21_283EN