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.