In the JournalsPerspective

Adjuvant Cytokine-Induced Killer Cell Therapy Improves Survival in Postoperative Breast Cancer

An analysis of patients with postoperative breast cancer has shown increased OS and RFS among patients who received adjuvant therapy with cytokine-induced killer cell infusion, according to the results of a retrospective study published in Journal of ImmunoTherapy of Cancer.

Additionally, the study showed that PD-L1 expression was an independent prognostic factor that predicted survival benefit from CIK treatment.

“A series of studies has shown that CIK-based treatment could significantly improve the prognosis of both hematologic malignancies and solid tumors, including breast cancer,” Zi-Qi Zhou, with Sun Yat-Sen University Cancer Center, and colleagues wrote. “However, not all tumor patients who receive CIK cell infusion exhibit improved outcomes; some patients are nonresponsive. Therefore, we sought to investigate what methods can identify patients who are suitable for CIK cell treatment.”

The investigators conducted a retrospective analysis of medical records of women who had CIK cell immunotherapy after undergoing surgery for breast cancer at Sun Yat-Sen University Cancer Center in Guangzhou, China, between December 1, 2009, and December 31, 2013. Surgeries included quadrantectomy or mastectomy and axillary lymph node dissection. The records review yielded 301 qualified patients, with 150 patients who received adjuvant CIK immunotherapy (CIK group) and 160 patients who did not (control group). Most patients were older than 50 years in both groups and had stage 3 TNM tumors. Most patients also expressed PD-L1 in both groups (n = 118 in the CIK group; n = 106 in the control group).

Follow-up visits were conducted every 3 months for the first 2 years after surgery, followed by every 6 months for 2 years and then once annually.

Patients who received adjuvant CIK immunotherapy had their blood collected about 2 weeks after surgery, once their blood levels had returned to normal. The cells were then cultured with CIK cells harvested on day 14 of the process. Patients were then infused with four cycles of autologous CIK cells with a 2-week interval between every 2 cycles.

Patient tissue samples also underwent subsequent immunohistochemical analysis to determine PD-L1 expression.

The investigators’ analysis showed that 5-year OS was significantly better in the CIK group compared with the control group (85.7% vs. 72.3%; HR = 0.502; 95% CI, 0.309-0.819). Five-year RFS rates were also significantly better in the CIK group compared with the control group (80.8% vs. 68.6%; HR = 0.563; 95% CI, 0.359-0.884).

Multivariate analysis of the results showed that TNM stage and PD-L1 expression were independent prognostic factors for patients who received adjuvant CIK immunotherapy.

The 5-year OS rate of patients in the PD-L1-postivie group was 95.2%, and the 5-year RFS rate was 87.6%. Five-year OS and RFS rates in the PD-L1-negative group were 77.1 and 76.4%, respectively.

“The Cox proportional regression analyses showed that PD-L1 expression was an independent prognostic factor for postoperative CIK treatment,” Zhou and colleagues wrote.

“In addition, when 5% was used as a stratification standard to distinguish all the patients, people who received CIK cell infusion had prolonged OS and RFS in the PD-L1 5% expression cohort. Therefore, we think that over 5% PD-L1 tumor expression can be used as a predictor of CIK-assisted immunotherapy for postoperative breast cancer patients after comprehensive treatment.”

Twelve patients experienced adverse events related to CIK cell treatment. Treatment-related adverse events included fever (4 patients), fatigue and anorexia (3 patients), nausea/vomiting (1 patient) and transient hypertension (1 patient). The median time to onset of therapy-related adverse events was 4.5 hours (range, 0.5–30 hours), with a median duration of 12 hours (range, 0.5–36.0 hours).

“We confirmed that CIK immunotherapy could improve the prognosis of breast cancer patients and for the first time revealed that PD-L1 expression in the tumor is as an indicator of adjuvant CIK therapy for postoperative breast cancer,” the investigators wrote. “Our findings on the relationship between PD-L1 expression and CIK therapy [c]ould provide new insights into the theory of tumor immunotherapy. Additional multicenter and large-sample validation studies are required to verify our results.” – by Drew Amorosi

Disclosures: The authors report no relevant financial disclosures.

An analysis of patients with postoperative breast cancer has shown increased OS and RFS among patients who received adjuvant therapy with cytokine-induced killer cell infusion, according to the results of a retrospective study published in Journal of ImmunoTherapy of Cancer.

Additionally, the study showed that PD-L1 expression was an independent prognostic factor that predicted survival benefit from CIK treatment.

“A series of studies has shown that CIK-based treatment could significantly improve the prognosis of both hematologic malignancies and solid tumors, including breast cancer,” Zi-Qi Zhou, with Sun Yat-Sen University Cancer Center, and colleagues wrote. “However, not all tumor patients who receive CIK cell infusion exhibit improved outcomes; some patients are nonresponsive. Therefore, we sought to investigate what methods can identify patients who are suitable for CIK cell treatment.”

The investigators conducted a retrospective analysis of medical records of women who had CIK cell immunotherapy after undergoing surgery for breast cancer at Sun Yat-Sen University Cancer Center in Guangzhou, China, between December 1, 2009, and December 31, 2013. Surgeries included quadrantectomy or mastectomy and axillary lymph node dissection. The records review yielded 301 qualified patients, with 150 patients who received adjuvant CIK immunotherapy (CIK group) and 160 patients who did not (control group). Most patients were older than 50 years in both groups and had stage 3 TNM tumors. Most patients also expressed PD-L1 in both groups (n = 118 in the CIK group; n = 106 in the control group).

Follow-up visits were conducted every 3 months for the first 2 years after surgery, followed by every 6 months for 2 years and then once annually.

Patients who received adjuvant CIK immunotherapy had their blood collected about 2 weeks after surgery, once their blood levels had returned to normal. The cells were then cultured with CIK cells harvested on day 14 of the process. Patients were then infused with four cycles of autologous CIK cells with a 2-week interval between every 2 cycles.

Patient tissue samples also underwent subsequent immunohistochemical analysis to determine PD-L1 expression.

The investigators’ analysis showed that 5-year OS was significantly better in the CIK group compared with the control group (85.7% vs. 72.3%; HR = 0.502; 95% CI, 0.309-0.819). Five-year RFS rates were also significantly better in the CIK group compared with the control group (80.8% vs. 68.6%; HR = 0.563; 95% CI, 0.359-0.884).

Multivariate analysis of the results showed that TNM stage and PD-L1 expression were independent prognostic factors for patients who received adjuvant CIK immunotherapy.

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The 5-year OS rate of patients in the PD-L1-postivie group was 95.2%, and the 5-year RFS rate was 87.6%. Five-year OS and RFS rates in the PD-L1-negative group were 77.1 and 76.4%, respectively.

“The Cox proportional regression analyses showed that PD-L1 expression was an independent prognostic factor for postoperative CIK treatment,” Zhou and colleagues wrote.

“In addition, when 5% was used as a stratification standard to distinguish all the patients, people who received CIK cell infusion had prolonged OS and RFS in the PD-L1 5% expression cohort. Therefore, we think that over 5% PD-L1 tumor expression can be used as a predictor of CIK-assisted immunotherapy for postoperative breast cancer patients after comprehensive treatment.”

Twelve patients experienced adverse events related to CIK cell treatment. Treatment-related adverse events included fever (4 patients), fatigue and anorexia (3 patients), nausea/vomiting (1 patient) and transient hypertension (1 patient). The median time to onset of therapy-related adverse events was 4.5 hours (range, 0.5–30 hours), with a median duration of 12 hours (range, 0.5–36.0 hours).

“We confirmed that CIK immunotherapy could improve the prognosis of breast cancer patients and for the first time revealed that PD-L1 expression in the tumor is as an indicator of adjuvant CIK therapy for postoperative breast cancer,” the investigators wrote. “Our findings on the relationship between PD-L1 expression and CIK therapy [c]ould provide new insights into the theory of tumor immunotherapy. Additional multicenter and large-sample validation studies are required to verify our results.” – by Drew Amorosi

Disclosures: The authors report no relevant financial disclosures.

    Perspective
    Filipa Lynce

    Filipa Lynce

    The use of immune checkpoint inhibitors as monotherapy in the treatment of metastatic breast cancer has been somewhat disappointing and associated with modest response rates.

    Several strategies have been employed to increase the activation of the immune system, including combination with other immunotherapy agents, chemotherapy, targeted therapies, radiotherapy or use of other types of cell-based immunotherapies, such as vaccines or chimeric antigen receptor (CAR) T cells. In this study, Zhou and colleagues report on the safety and efficacy of cytokine-induced killer (CIK) cells, an effective cell-based immunotherapy, in 150 patients with nonmetastatic breast cancer.

    The focus of this report is on biomarker selection and the investigators concluded that PD-L1 positivity, defined as 5% in the tumor, was predictive of response to CIK cell infusion. Biomarker selection to predict response to immunotherapy continues to be an important challenge in the treatment of breast cancer.

    Earlier this year, the FDA approved the first immune checkpoint inhibitor for the treatment of breast cancer. It approved a combination of atezolizumab (Tecentriq; Genentech) with paclitaxel protein-bound for patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) with PDL1 expression 1% in tumor-infiltrating immune cells (IC) based on results of the phase III Impassion130 study. In a biomarker subgroup analysis of this study, PD-L1 expression on tumor cells did not provide additional information beyond PD-L1 IC expression.

    More recently, the results of the phase III KEYNOTE-522 trial presented at ESMO 2019 showed that the addition of pembrolizumab (Keytruda; Merck) to standard neoadjuvant chemotherapy significantly increased the pCR rate compared with chemotherapy and placebo in early-stage TNBC. In this study, however, the anti-tumor activity was observed regardless of the PD-L1 expression status. As we continue our efforts to bring immunotherapy to clinical practice and to the appropriate patients, the identification of biomarkers predictive of response and toxicity, as well as the best antibodies and cut-offs, remains crucial.

    Reference:

    Schmid P, et al. Abstract LBA8. Presented at: European Society for Medical Oncology; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

    • Filipa Lynce, MD
    • Assistant professor of medicine, Georgetown University
      Medical oncologist at MedStar Washington Hospital Center and
      Lombardi Comprehensive Cancer Center
      HemOnc Today Next-Gen Innovator

    Disclosures: Disclosures: Lynce reports unpaid advisory board roles with Bristol-Myers Squibb and Jounce Therapeutics and institutional research funding from Bristol-Myers Squibb, Calithera, Immunomedics, Pfizer and Regeneron.

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