Introduction
Adoptive T cell therapy (ACT) is a major immunotherapy and has been shown to be a powerful approach to cancer treatment [1]. Cytokine-induced killer (CIK) cells are polyclonal T effector cells sharing immunological properties and receptors with natural killer (NK) cells. They are attracting increasing interest for their ability to perform non-MHC-restricted cytolytic activities towards susceptible autologous and allogeneic cancer cells [2-3]. CIK cell treatment has an adjuvant immunomodulatory effect by prolonging survival in several types of cancer patients who undergo curative treatment [4]. Adjuvant immunotherapy with autologous cytokine-induced killer cells have evidence clinical effects in hepatocellular carcinoma [5]. Moreover, a phase I study result showed that the activity of PD-1 blockade-activated CIK cells in patients with advanced solid tumors was still unsatisfactory, as the objective response rate (ORR) across the 31 enrolled patients was 22.5%, with only two patients (6.4%) showing a complete response (CR) and five patients (16.1%) showing a partial response (PR) [6]. Therefore, a detailed analysis is necessary to determine which patients will have a good response to CIK cell therapy that maintains sustained antitumor effects.
The state of T cell differentiation is an important factor that influences immune activity after ACT. It is likely that innate humoral and cellular immune deficiencies, including inherent T cell defects, lead to T cell exhaustion and treatment failure. Cultured T cells with the phenotype of CD45RO−, CCR7+, CD45RA+ and CD62L+ are characteristic of naïve T cells. Naïve T cells are a subset of less differentiated T cells with strong self-renewal and multipotent capacity to derive effector T cells that are specific for multiple viral and self-tumor antigens [7-9]. Naïve T cells resist terminal differentiation and maintain high replicative potential that have shown great efficacy in clinical trials, so they may be a superior subset for use in adoptive immunotherapy. For ACT, because most protocols require that peripheral blood lymphocytes be cultured for at least 12‒14 days ex vivo , we hypothesized that the number of naïve T cells among patients’ peripheral blood lymphocytes may influence the culture results including T cell cytotoxicity and amplification. ACT utilizes CIK cells, genetically engineered T cells with chimeric antigen receptors (CARs), T cells and T cell receptor (TCR) therapy, but the blood-based biomarkers that may be useful for predicting clinical response are still completely unclear. CD27+PD-1-CD8+ T cell populations of less differentiated cells have been used as blood-based biomarkers to predict clinical response in CAR T cell therapy [10]. Pre-clinical studies have also reported that naïve and less differentiated T cells have strong cell activity for long-term immune response [11-16]. Moreover, the increased persistence of adoptively transferred cells appears to be dependent upon the acquisition of naïve or less differentiated populations [17-20].
Naïve and less differentiated T cells have strong self-renewal and multipotent capacity to derive effector T cells and are specific for multiple viral and self-tumor antigens [21]. Blood-based biomarkers are important for predicting clinical response to immunotherapy. In CIK cell therapy, it is unclear whether naïve and less differentiated T cells will work as blood-based biomarkers to determine which patients will have a good response. We hypothesized that patients with high absolute numbers of naïve T cells in circulating blood will have a better response to CIK cell therapy. This clinical trial was therefore designed to understand whether naïve T cells in circulating blood can serve as pretreatment biomarkers to determine which patients will have a better response to CIK cell therapy.