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Advances in Evidence-Based Cancer Adoptive Cell Therapy Review Article Page 1 of 18 Advances in evidence-based cancer adoptive cell therapy Chunlei Ge1, Ruilei Li1, Xin Song1, Shukui Qin2 1Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China; 2Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing 210002, China Contributions: (I) Conception and design: X Song; (II) Administrative support: S Qin; (III) Provision of study materials or patients: C Ge; (IV) Collection and assembly of data: R Li; (V) Data analysis and interpretation: C Ge; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Professor Xin Song. Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming 650118, China. Email: [email protected]; Professor Shukui Qin. Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing 210002, China. Email: [email protected]. Abstract: Adoptive cell therapy (ACT) has been developed in cancer treatment by transferring/infusing immune cells into cancer patients, which are able to recognize, target, and destroy tumor cells. Recently, sipuleucel-T and genetically-modified T cells expressing chimeric antigen receptors (CAR) show a great potential to control metastatic castration-resistant prostate cancer and hematologic malignancies in clinic. This review summarized some of the major evidence-based ACT and the challenges to improve cell quality and reduce the side effects in the field. This review also provided future research directions to make sure ACT widely available in clinic. Keywords: Adoptive cell therapy (ACT); non-specific cell therapy; specific cell therapy; dendritic cell-based therapy Submitted Mar 10, 2016. Accepted for publication Dec 28, 2016. doi: 10.21037/cco.2017.02.07 View this article at: http://dx.doi.org/10.21037/cco.2017.02.07 Introduction patients with metastatic castration-resistant prostate cancer in phase III clinical trials (3). Ipilimumab (4), a human Cancer is a major global public health problem and the monoclonal antibody that activates the immune system by number of newly diagnosed cases continues to increase due cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), to aging and growth of worldwide populations. Although has increased the OS rate of patients with melanoma by advancement in early detection, prevention, and treatment 45.6% at 12 months, 33.2% at 18 months, and 23.5% at options, cancer is still the second cause of human mortality. 24 months. Programmed cell death 1 (PD-1) is another To date, most cancers are clinically diagnosed at the negative co-stimulatory receptor expressed primarily on the advanced stages of diseases, which result in curable surgery surface of activated T cells (5,6) and anti-PD-1 antibodies not an option, while chemotherapy and radiotherapy are not (pembrolizumab and nivolumab) were able to not only effective in cure of most cancer patients. During the past increase OS of patients with metastatic melanoma (7,8), decade, development of modern medicine, such as target but also to reach better response rate and progression-free therapy has still relatively short-term benefits for selected survival (PFS) of patients with advanced, previously treated patients (1). squamous-cell NSCLC (9-11). Thus, immunotherapy In recent years, different studies demonstrated that shows encouraging in control of human cancers. enhancement of cytotoxicity to target the cellular immune Adoptive cell therapy (ACT) is another potentially useful system could help clinicians to fight human cancer (2). approach to treat human cancers (12) and previous studies For instance, sipuleucel-T, the first therapeutic cancer showed that such a cancer immunotherapy can include non- vaccine approved by US FDA, is an autologous active specific cell therapy [lymphokine-activated killer (LAK) cell immunotherapy to improve overall survival (OS) of cells, cytokine-induced killer (CIK) cells and natural killer © Chinese Clinical Oncology. All rights reserved. cco.amegroups.com Chin Clin Oncol 2017;6(2):18 Page 2 of 18 Ge et al. Evidence-based cancer adoptive cell therapy cells (NK)], specific cell therapy [cytotoxic T lymphocytes metastatic melanoma and partial responses (PRs) occurred (CTLs), tumor-infiltrating lymphocytes (TILs), T cell in 9 patients with pulmonary or hepatic metastases from therapy with modified T cell receptor (TCR) genes, T cell melanoma, colon cancer, or renal-cell cancer and in patients therapy with modified chimeric antigen receptors (CAR) with primarily unresectable lung adenocarcinoma. In 1988, genes] and so on. ACT is to stimulate body own immune another study summarized a series of clinical trials using system in order to trigger antitumor immune response, high-dose of IL-2 alone or in combination with LAK (17). and eventually enable natural abilities to better recognize, Of 221 patients, 16 had a CR in patients with metastatic target, and, finally, eliminate cancer cells from human body. cancer and an additional 26 had a partial tumor regression Compared to other forms of cancer immunotherapy, ACT (PR). Based on these studies, LAK cell therapy has been has multiple advantages, e.g., long-term benefit after short- considered to be effective against metastatic melanoma, term treatment and slight fewer adverse events. Although renal cell carcinoma, and other advanced solid tumors. dendritic cells (DCs) and CTLs therapy have made a great However, in another randomized clinical trial, the result progress, clinical applications are still somewhat limited. suggested a trend toward improving survival when IL-2 Recently, the genetic-modified T cells expressing specific was given together with LAK cells to melanoma patients, TCRs or CARs are just now entering the clinical trials but not occur in patients with renal cell carcinoma (21). and the data have shown a great potential for high avidity Moreover, a randomized phase III trial of IL-2 with or to tumor-associated antigens and long-lasting anti-tumor without LAK cells in treatment of patients with advanced responses, which encourages researchers to continuously renal cell carcinoma demonstrated that there was no study feasibility of this therapy in human cancers (13-15). difference in treatment response (P=0.61) and survival (P=0.67) Thus, our current review summarized the most recent between these two treatment arms and more patients on the advances and discussed and predicted the future research LAK arm experienced pulmonary toxicity (22). In addition, directions in this field. several other studies showed the safety and efficacy of LAK cell therapy in patients with malignant gliomas (23-25). In one study, a median OS of 31 patients with glioblastoma Non-specific cell therapy multiforme (GBM) was 17.5 months versus 13.6 months Non-specific cell therapy is an immunotherapy to non- in control group (23). Boiardi et al. reported that the specifically activate immune cells to induce their “non”- focal injection of LAK cells and IL-2 in 9 recurrent GBM specific antitumor immune response to reject and destroy patients were well-tolerated and the response rate was 33%, cancer cells. Based on different types of immune cells although the median OS of patients didn’t show significant involved, non-specific cell therapy can be divided into LAK improvement (26). cell, CIK cell, and NK cell-mediated antitumor therapies. Thus, although LAK cell therapy seemed to effectively This non-specific cell therapy was used to treat different kill some tumor cells, high toxicity caused by high dose human cancers clinically (16-18). of IL-2 (such as vascular leakage and severe hypotension) (26,27) limited its clinical usage. LAK cell-mediated non-specific cell therapy CIK cell-mediated non-specific cell therapy Grimm and his colleagues first reported in 1982 (19) non- specific killer cells generated by culture of peripheral blood CIK cells are obtained by isolated from PBMCs and then mononuclear cells (PBMC) with high dose of interleukin-2 stimulated with a cocktail of interferon-gamma (IFN-γ), (IL-2), which was named as LAK cells. LAK cells contain anti-CD3 monoclonal antibody, and IL-2 in a stepwise in a a mixture of T cells and NK cells, both of which are not time-dependent ex vivo culturing process for approximately restricted by the major histocompatibility complex (MHC) 2 weeks (28). CIK cells are a mixture of cells with non- against a broad range of tumor cells in vitro (16,20) . MHC-restricted cytolytic activity, including CD3+CD56− Thereafter, Rosenberg and associates (16) showed effects T cells and CD3+CD56+NK-T cells, and a relatively minor of autologous LAK cells and IL-2 on patients with advanced population of CD3−CD56+NK cells (29-31). Compared cancers in whom standard therapy had failed. The objective to standard IL-2 stimulated LAK cells, CIK cells have tumor regression achieved in 11 out of 25 patients, i.e., a enhanced antitumor cytotoxic activity by over 70-fold (32). complete tumor regression (CR) occurred in 1 patient with The lytic activity can be further enhanced by addition of © Chinese Clinical Oncology. All rights reserved. cco.amegroups.com Chin Clin Oncol 2017;6(2):18 Chinese Clinical Oncology, Vol 6, No 2 April 2017 Page 3 of 18 IL-1, IFN-γ, IL-7, IL-15, and other cytokines (33-36). alone or with sequential radiotherapy and 45 patients To date, CIK cells have been evaluated as an adoptive cell received chemotherapy with/without radiotherapy and immunotherapy for cancer patients in numerous clinical sequential CIK infusion. The 1-, 2-, 3-, and 4-year disease- trials (summarized in Table 1). In the first phase I clinical free survival (DFS) rates in the CIK group were 97.7%, study, autologous immunological effector cells were 90.1%, 83.4%, and 75.2%, respectively, vs. 88.9%, 64.4%, transfected with the IL-2 gene and to treat patients with 62.1%, and 56.4%, respectively, in the control group.
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