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Disease Markers
Volume 2019, Article ID 3425291, 11 pages
https://doi.org/10.1155/2019/3425291
Research Article

Efficiency of CAR-T Therapy for Treatment of Solid Tumor in Clinical Trials: A Meta-Analysis

1Department of Surgical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
2Department of General Surgery, Xi’an No. 3 Hospital, Xi’an, Shaanxi, China

Correspondence should be addressed to Dongmin Chang; moc.anis@mdgnahc_rd

Received 21 August 2018; Revised 23 October 2018; Accepted 2 December 2018; Published 11 February 2019

Academic Editor: Giuseppe Murdaca

Copyright © 2019 Bin Hou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background. Chimeric antigen receptor T (CAR-T) cell therapy has achieved unprecedented success among hematologic tumors, but its role in treating solid tumors is still unclear. Methods. A comprehensive search of electronic databases up to June 1, 2018, was carried out by two independent reviewers. We included studies which focused on the association between CAR-T cell therapy and patient response rate and survival time in solid tumors. Results. 22 studies with 262 patients were included in our meta-analysis. The overall pooled response rate of CAR-T cell therapy was 9% (95% confidence interval (CI): 4-16%). Subgroup analysis (analyses) demonstrated that CAR-T therapy could perform its best therapeutic effect on neuroblastoma, while barely works among gastrointestinal malignancies. Moreover, the treatment efficacy was not significantly impacted by different treatment strategies (lymphodepletion before T cell infusion, transfection method, cell culture duration, persistence of CAR-T cells, transfection efficacy, total cell dose, and administration of IL-2). Only T cell culture duration was associated with better clinical prognosis. Conclusions. Although CAR-T cell therapy did not have satisfactory responses in solid tumors, researchers were still holding an optimistic attitude towards its future efficacy with more modifications of its structure.

1. Introduction

With the rapid development of molecular biology, the concept of cancer treatment makes great progress. Chimeric antigen receptor T (CAR-T) cell therapy, whose initial conceptualization was put forward in the late 1980s, has been approved by FDA in 2017 as the first genetically engineered cellular treatment for pediatric and young adult acute lymphoblastic leukemia (ALL) [1]. This therapy, in theory, allows CARs, which are artificially engineered receptors that could express on cell surface with non-HLA-restricted tumor antigens, to activate T cells and guide them specifically to tumor cells to perform their function. For now, CD-19 is the most attractive target in this immunotherapy. Encouragingly, T cells expressing the CD19-CARs have achieved unprecedented therapeutic efficacy in malignant hematological diseases with up to 90% complete remission rate in ALL and more than 60% in non-Hodgkin’s lymphoma (NHL) [2]. In a phase II trial conducted by Neelapu et al. [3], 111 patients with B cell lymphoma were recruited and they accepted anti-CD19 CAR-T cell therapy. The objective response rate and the complete response rate were 82% and 54%, respectively.

Enlightened by the idea of adoptive immunotherapy and its great success in treating hematological malignancies, a number of preclinical CAR-T cell therapy trials have been carried out in solid tumors. However, the results were variable in different tumors with different therapeutic strategies. Louis et al. [4], for example, used CAR-T cells in treating neuroblastoma. They found that 4 out of 19 (52.9%) patients achieved objective clinical responses and 3 of them even got complete remission. O’Rourke et al. [5], however, treated recurrent glioblastoma patients with anti-EGFRvIII CAR-T cells. None of the 10 patients has positive response (partial response or complete response) to this therapy. Although the results were unsatisfactory, researchers still believed that CAR-T cell therapy was a promising method for tumor treatment.

Owing to the variability of those clinical trials, it is extremely necessary to analyze the impact of CAR-T therapy on tumor treatment collectively. Currently, there are three meta-analyses concerning the efficacy and safety of CAR-T cell therapy in hematological malignancies [68]. Solid tumor treatment efficacy, however, has no satisfactory synthesis data yet. Thus, we conducted this systemic review and meta-analysis to comprehensively investigate the treatment efficacy of CAR-T cell therapy in solid tumors. We also used subgroup analysis to explore the factors that could affect the efficacy of this therapy. Our team focused on the evaluation of the clinical outcomes of different treatments [9]. Therefore, we hoped our results could help researchers and clinicians in clinical trial design.

2. Materials and Methods

2.1. Data Sources

A comprehensive search in the PubMed database up to June 1, 2018, was undertaken using a combination of the following keywords: “CAR-T therapy,” “chimeric antigen receptor T cell,” “solid tumor,” and “prognosis.” Meanwhile, abstracts from the American Society of Clinical Oncology (ASCO) using the same search terms were evaluated. An independent search of the Embase database was also carried out.

2.2. Study Selection

The following criteria were considered in this research: (1) prospective or retrospective cohort studies of patient with nonhematologic solid tumors and (2) assessment of the prognostic effect of CAR-T therapy on complete response rate or partial response rate, overall survival (OS), progression-free survival (PFS), and alive with disease (AWD). Articles were excluded with any of the following criteria: (1) patient with hematologic malignancies; (2) animal experiments and non-English studies; (3) duplicated data; (4) comments, reviews, or meta-analyses without original data; and (5) no clinical outcome.

2.3. Data Extraction

Two independent investigators reviewed eligible articles and extracted data from studies. Gender, age, type of solid tumor, gene transduction method, T cell culture time, original T cell sources, lymphodepletion, IL-2 administration for patient, total infused CAR+ T cell number (data in cells/kg or cell/m2 were multiplied by 60 kg or 1.73m2, respectively), CAR+ T cell persistence time, and clinical outcomes of patients with CAR-T therapy were collected from each study. The primary endpoint was the response rate of CAR-T immunotherapy in this meta-analysis. Therapy response was defined by the RECIST 1.1 and immune-related response criteria.

2.4. Statistical Analysis

All statistical analysis was performed by the R software version 3.3.0 (http://www.r-project.org). All statistical tests were two-sided, and was considered statistically significant. The heterogeneity of data among included studies was examined by using Cochran’s -test and Higgins’ statistic. We defined insignificant heterogeneity if the value was <50% and we used a fixed-effect model to calculate the parameters. If value is ≥50%, we discerned that a significant heterogeneity existed and a random-effect model was applied to the data. Subgroup analyses were conducted according to tumor sites (gastrointestinal tumor, hepatobiliary and pancreatic tumor, neurologic tumor, and other tumors), lymphodepletion before T cell infusion (yes or no), transfection method (by lentivirus or retrovirus), cell culture duration (<14 days vs. ≥14 days), persistence of CAR-T cells (<4 weeks vs. ≥4 weeks), transfection efficacy (<50% vs. ≥50%), total cell dose (<109 vs. ≥109), and administration of IL-2 (yes or no). Assessment of publication bias was examined by the use of funnel plots and confirmed by Egger’s and Begg’s test.

3. Results

3.1. Study Characteristics

Publications were initially identified following our search strategy. After removing duplicated publications, 1243 studies were selected for further analysis. We next screened the title and abstract of each article. Reviews, in vitro studies, and nonhuman studies were excluded from our analysis. Consequently, 291 eligible studies received full-text evaluation. Among them, 27 studies with insufficient survival data were excluded from this analysis. Thus, a total of 22 studies with 262 patients fulfilled our inclusion criteria and were enrolled in our study; only 82 patients from 8 clinical researches had OS data. The selection process is shown in Figure 1.

Figure 1: Flow diagram of study selection process.

Table 1 summarizes the baseline characteristics of included studies. Of all eligible studies, five studies reported on neurological tumors () [4, 5, 1014], followed by hepatobiliary and pancreatic cancers () [1519], melanoma and sarcoma () [2022], gastrointestinal malignancies () [23, 24], prostate cancer () [25], breast cancer () [26], non-small-cell lung cancer () [27], and others [28]. Most of the patients enrolled in this analysis had advanced tumor (stages III-IV). There were two main transfection methods (lentivirus and retrovirus) with various cancer-specific antigens (EGFR, CEA, HER2, etc.) used in these studies. All of the patients were infused with autologous T cells. 134 (51.1%) patients received lymphodepletion before CAR-T cell infusion and 96 (36.6%) patients had IL-2 treatment during CAR-T therapy.

Table 1: The baseline characteristics of eligible clinical researches.
3.2. Treatment Response

The response rate of CAR-T cell therapy in each study varied, ranging from 0% to 100%. Six patients (2.3%) got complete response and 25 patients (9.5%) achieved partial remission. As shown in Figure 2, the overall remission rate of 9% (95% CI: 4%-16%) was observed in a random-effect model with significant heterogeneity among studies (, ).

Figure 2: Forest plot for response rates and confidence intervals in each study and the overall.

Subgroup analyses were carried out according to tumor sites (gastrointestinal tumor, hepatobiliary and pancreatic tumor, neurologic tumor, and other tumors), lymphodepletion before T cell infusion (yes or no), transfection method (by lentivirus or retrovirus), cell culture duration (<14 days vs. ≥14 days), persistence of CAR-T cells (<4 weeks vs. ≥4 weeks), transfection efficacy (<50% vs. ≥50%), total cell dose (<109 vs. ≥109), and administration of IL-2 (yes or no). Our results demonstrated that the main source of heterogeneity in our analyses derived from different tumor site (). As shown in Figure 3, the pooled response rate reached 11% (95% CI: 1%-32%, ) in hepatobiliary and pancreatic cancer, 12% (95% CI: 3%-27%, ) in neurologic tumor, and 12% (95% CI: 5%-21%, ) in other tumors. Notably, CAR-T cell therapy showed frustrated treatment effect among gastrointestinal cancer. We did not find significant heterogeneity within the rest of subgroups (all ), but the statistic for heterogeneity was high in each group, indicating the heterogeneous trend in each study (Table 2).

Figure 3: Forest plot for response rates and confidence intervals among different tumor sites.
Table 2: Pooled response rate for CAR-T cell therapy according to subgroup analyses.

Sensitivity analysis using a “one-study removed” model was conducted to testify the stability of our result. As shown in Figure 4, the observed effect size of response rate was not significantly affected by removing a single study each time. Publication bias was not found by visual inspection of the funnel plot (Figure 5) and confirmed by Begg’s test and Egger’s tests (all ). Thereby, the reliability of our results could be confirmed.

Figure 4: Sensitivity analysis using a “one-study removed” model.
Figure 5: Funnel plot of publication bias in the meta-analysis.
3.3. Patients’ Prognosis

The median survival time of patients with CAR-T therapy () was 576 days. The one-year and three-year OS rates were 64.1% and 20.4%, respectively (Figure 6(a)). Then we compared clinical outcomes of patients who accepted different CAR-T therapies. We divided the 82 patients into different groups according to total T cell dose, transduction efficiency, and T cell culture duration. The results showed that only T cell culture duration was associated with better clinical prognosis. As shown in Figure 6(b), patients with T cell culture duration more than 14 days () had better treatment outcomes than those with T cell culture duration less than 14 days () (median survival time: 723 days vs. 451 days, ). Of note, patients with lower infused CAR+ T cell dose tend to have better prognosis than those with higher T cell dose, although the result is insignificant (584 vs. 210 days, ) (Figure 6(c)). The survival curve of patients with different transduction efficiency is shown in Figure 6(d).

Figure 6: Overall survival (OS) curves. (a) Survival curve of patients with CAR-T therapy. (b) Survival curve of different T cell culture time. (c) Survival curve of different CAR-T cell dose. (d) Survival curve of different transduction efficiency.

4. Discussion

CAR-T cell therapy opens a new era for cancer treatment by using artificial modified autologous immune cells. Compared to previous conservative treatments, such as radiotherapy and chemotherapy, this therapeutic approach has the ability to recognize unique antigen expressed in the tumor surface (like a monoclonal antibody) and subsequently induces full T cell activation. By doing this, cancer cells are eliminated specifically while normal somatic cells are well preserved. To date, this approach has made a great success in treating hematological malignancies. However, its therapeutic effect in solid malignancies is unsatisfactory. Although several small-size clinical trials have been made, there is no systematic review to evaluate its efficacy and safety. In this meta-analysis, with well-designed selection method and strictly statistical analysis, we concluded that the response rate of CAR-T cell therapy among solid tumors reaches 9% (95% CI: 4%-16%). Moreover, we observed that the best therapeutic effect of CAR-T cell therapy on advanced cancers was observed in neuroblastoma (response rate: 33%, 95% CI: 1%-91%). Although the outcome was a little bit frustrating, it was still too early to draw a conclusion of its efficacy in solid tumors. There are still great potentials for us to tap.

The formation of solid tumors is different from that of hematological tumors; therefore, certain obstacles should be taken into consideration when clinicians are trying to transfer CAR-T cell therapy from liquid cancers to solid tumors. Unlike hematological tumors, solid tumor cells are rarely present in the circulation system, but tumor cells could form several discrete foci where T cells are obviously difficult to infiltrate. In addition to the physical barriers, chemokines that are secreted by solid tumor cells are usually abnormal, which may lead to insufficient T cell recruitment [29]. To address this issue, scientists try to infuse CAR-T cells by intratumoral routes and have achieved relatively satisfactory results with acceptable toxicity in a mouse model [30]. Moreover, some molecular modifications on T cells have been made to enhance the efficacy of T cell recruitment [16, 3133]. After T cells infiltrated the tumor, intratumoral T cells usually cannot perform their antitumor function very well. Two checkpoint molecules, PD-1 and CTLA-4, particularly contribute to this phenomenon. A number of tumor cells could express the ligand of those two molecules and consequently lead to immune activation suppression [3436]. To solve this problem, researchers attempt to combine CAR-T cell therapy with immune checkpoint blockade [3739]. Although all of those methods are still in preclinical trials, some of them may lead to meaningful improvement for CAR-T cell therapy with solid malignancies.

Safety is another vital criterion to evaluate a novel cancer-treating strategy. In CAR-T cell immunotherapy, on-target off-tumor toxicities and cytokine-released syndrome (CRS) are the two major adverse events. Because most of the solid tumors have epithelial origin, it is difficult to find an antigen specifically expressed in the tumor cell surface while being absolutely absent in normal epithelial cells. Therefore, off-target toxicities happened. The main character of toxicity is tissue or organ damage induced by the overflow of inflammatory cytokines. The symptoms of CRS are more variable and some of them could be long-lasting and life-threatening. The underlying mechanism of CRS is still ambiguous. Except for clinical examination markers used in clinical practice, different host status and tumor microenvironment may contribute to the occurrence of CRS. Many organs and systems in our body, like the circulatory system, respiratory system, digestive system, and nervous system, get involved in those adverse events. Some articles [17, 22, 24, 27] included in our analysis found that the toxicities may positively correlate with infusion dosage, but the adverse effect is acceptable for the majority of them and they could be alleviated by medical interference. However, severe adverse effects (grade 3 and grade 4) were reported in 80% (12/15) of the included articles. Most of them were neurotoxicity (such as fatigue, dizziness, dysgeusia, and headache) and nonspecific symptoms (fever and muscle aches, etc.). Feng et al. [17] reported that a patient with advanced cholangiocarcinoma broke out severe complications after CAR-CD133 T cell infusion, including an intermittent upper abdominal dull pain, chills, fever, and rapidly deteriorative grade 3 systemic subcutaneous hemorrhages and congestive rashes together with serum cytokine release, which needed emergent medical intervention including intravenous methylprednisolone. Our analysis also showed that patients with lower infused CAR+ T cell dose tend to have better prognosis than those with higher T cell dose (584 vs. 210 days, ). We should fully notice that enhancing treatment dosage may also increase the risk of experiencing an adverse drug reaction. Collectively, most complications could be attenuated successfully by standard supportive therapy, but any benefit of CAR-T cell therapy must be weighed against the risk of severe or even life-threatening complications. The toxicities and optimum therapeutic dosage remain a topic for further investigation.

Certain limitations should be taken into consideration. Firstly, CAR-T cell therapy for advanced solid tumors is a brand-new treatment strategy; for now it lacks large-scale clinical data to comprehensively evaluate its efficacy as well as safety. The main data in our analysis only contains response rate and short-term survival rate, whether patients could benefit from this treatment method is still uncertain. Furthermore, evaluation standards for adverse events are variable in each study; we only did descriptive analysis instead of statistical analysis in this part so that the result is inaccurate. There is still much work to be done before its wide clinical application.

5. Conclusions

Our meta-analysis indicates that the pooled response rate of CAR-T cell therapy in solid tumors reaches 9%. Although we have achieved some encouraging results, the construction improvement of CAR-T cells is still needed to fully recruit and activate immune cells to eliminate its target. There is still a long way to go before its application in clinical practice. However, by combining this new treatment method with updating technologies and lessons from retrospective studies, we believe CAR-T cell therapy will perform better clinical efficacy in treating solid tumor malignancies.

Data Availability

The data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Authors’ Contributions

Bin Hou and Yao Tang contributed equally to this work.

Acknowledgments

This research was supported by grants from the Science and Technology Foundation of Shaanxi Province (S2018-YF-ZDSF-0102).

References

  1. M. Ruella and M. Kalos, “Adoptive immunotherapy for cancer,” Immunological Reviews, vol. 257, no. 1, pp. 14–38, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. S. L. Maude, N. Frey, P. A. Shaw et al., “Chimeric antigen receptor T cells for sustained remissions in leukemia,” The New England Journal of Medicine, vol. 371, no. 16, pp. 1507–1517, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. S. S. Neelapu, F. L. Locke, N. L. Bartlett et al., “Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma,” The New England Journal of Medicine, vol. 377, no. 26, pp. 2531–2544, 2017. View at Publisher · View at Google Scholar · View at Scopus
  4. C. U. Louis, B. Savoldo, G. Dotti et al., “Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma,” Blood, vol. 118, no. 23, pp. 6050–6056, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. D. M. O’Rourke, M. L. P. Nasrallah, A. Desai et al., “A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma,” Science Translational Medicine, vol. 9, no. 399, article eaaa0984, 2017. View at Publisher · View at Google Scholar · View at Scopus
  6. F. Anwer, A. A. Shaukat, U. Zahid et al., “Donor origin CAR T cells: graft versus malignancy effect without GVHD, a systematic review,” Immunotherapy, vol. 9, no. 2, pp. 123–130, 2017. View at Publisher · View at Google Scholar · View at Scopus
  7. Y. Zhu, Y. Tan, R. Ou et al., “Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials,” European Journal of Haematology, vol. 96, no. 4, pp. 389–396, 2016. View at Publisher · View at Google Scholar · View at Scopus
  8. T. Zhang, L. Cao, J. Xie et al., “Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis,” Oncotarget, vol. 6, no. 32, pp. 33961–33971, 2015. View at Publisher · View at Google Scholar · View at Scopus
  9. W. Li, Y. Tang, Y. Song et al., “Prognostic role of pretreatment plasma D-dimer in patients with solid tumors: a systematic review and meta-analysis,” Cellular Physiology and Biochemistry, vol. 45, no. 4, pp. 1663–1676, 2018. View at Publisher · View at Google Scholar · View at Scopus
  10. N. Ahmed, V. Brawley, M. Hegde et al., “HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial,” JAMA Oncology, vol. 3, no. 8, pp. 1094–1101, 2017. View at Publisher · View at Google Scholar · View at Scopus
  11. N. M. Ahmed, V. S. Brawley, O. Diouf et al., “Autologous HER2 CMV bispecific CAR T cells for progressive glioblastoma: results from a phase I clinical trial,” Journal of Clinical Oncology, vol. 33, article 3008, 15_Supplement, 2015. View at Google Scholar
  12. C. E. Brown, D. Alizadeh, R. Starr et al., “Regression of glioblastoma after chimeric antigen receptor T-cell therapy,” The New England Journal of Medicine, vol. 375, no. 26, pp. 2561–2569, 2016. View at Publisher · View at Google Scholar · View at Scopus
  13. C. E. Brown, B. Badie, M. E. Barish et al., “Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma,” Clinical Cancer Research, vol. 21, no. 18, pp. 4062–4072, 2015. View at Publisher · View at Google Scholar · View at Scopus
  14. J. R. Park, D. L. DiGiusto, M. Slovak et al., “Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma,” Molecular Therapy, vol. 15, no. 4, pp. 825–833, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. G. L. Beatty, M. H. O’Hara, S. F. Lacey et al., “Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial,” Gastroenterology, vol. 155, no. 1, pp. 29–32, 2018. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Feig, J. O. Jones, M. Kraman et al., “Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 50, pp. 20212–20217, 2013. View at Publisher · View at Google Scholar · View at Scopus
  17. K. C. Feng, Y. L. Guo, Y. Liu et al., “Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma,” Journal of Hematology & Oncology, vol. 10, no. 1, p. 4, 2017. View at Publisher · View at Google Scholar · View at Scopus
  18. S. C. Katz, R. A. Burga, E. McCormack et al., “Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases,” Clinical Cancer Research, vol. 21, no. 14, pp. 3149–3159, 2015. View at Publisher · View at Google Scholar · View at Scopus
  19. B. Zhai, D. Shi, H. Gao et al., “A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC),” Journal of Clinical Oncology, vol. 35, 15_Supplement, p. 3049, 2017. View at Publisher · View at Google Scholar
  20. N. Ahmed, V. S. Brawley, M. Hegde et al., “Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma,” Journal of Clinical Oncology, vol. 33, no. 15, pp. 1688–1696, 2015. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Hegde, C. C. DeRenzo, H. Zhang et al., “Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma,” Journal of Clinical Oncology, vol. 35, 15_Supplement, p. 10508, 2017. View at Publisher · View at Google Scholar
  22. L. A. Johnson, R. A. Morgan, M. E. Dudley et al., “Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen,” Blood, vol. 114, no. 3, pp. 535–546, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. F. C. Thistlethwaite, D. E. Gilham, R. D. Guest et al., “The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity,” Cancer Immunology, Immunotherapy, vol. 66, no. 11, pp. 1425–1436, 2017. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Zhang, Z. Wang, Z. Yang et al., “Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers,” Molecular Therapy, vol. 25, no. 5, pp. 1248–1258, 2017. View at Publisher · View at Google Scholar · View at Scopus
  25. R. P. Junghans, Q. Ma, R. Rathore et al., “Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response,” The Prostate, vol. 76, no. 14, pp. 1257–1270, 2016. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Tchou, Y. Zhao, B. L. Levine et al., “Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer,” Cancer Immunology Research, vol. 5, no. 12, pp. 1152–1161, 2017. View at Publisher · View at Google Scholar · View at Scopus
  27. K. Feng, Y. Guo, H. Dai et al., “Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer,” Science China. Life Sciences, vol. 59, no. 5, pp. 468–479, 2016. View at Publisher · View at Google Scholar · View at Scopus
  28. Y. Wang, M. Chen, Z. Wu et al., “CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial,” OncoImmunology, vol. 7, no. 7, article e1440169, 2018. View at Publisher · View at Google Scholar · View at Scopus
  29. E. M. Hanson, V. K. Clements, P. Sinha, D. Ilkovitch, and S. Ostrand-Rosenberg, “Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells,” Journal of Immunology, vol. 183, no. 2, pp. 937–944, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. S. J. C. van der Stegen, D. M. Davies, S. Wilkie et al., “Preclinical in vivo modeling of cytokine release syndrome induced by ErbB-retargeted human T cells: identifying a window of therapeutic opportunity?” The Journal of Immunology, vol. 191, no. 9, pp. 4589–4598, 2013. View at Publisher · View at Google Scholar · View at Scopus
  31. J. A. Craddock, A. Lu, A. Bear et al., “Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b,” Journal of Immunotherapy, vol. 33, no. 8, pp. 780–788, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. M. H. Kershaw, G. Wang, J. A. Westwood et al., “Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2,” Human Gene Therapy, vol. 13, no. 16, pp. 1971–1980, 2002. View at Publisher · View at Google Scholar · View at Scopus
  33. E. K. Moon, C. Carpenito, J. Sun et al., “Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor,” Clinical Cancer Research, vol. 17, no. 14, pp. 4719–4730, 2011. View at Publisher · View at Google Scholar · View at Scopus
  34. H. Dong, S. E. Strome, D. R. Salomao et al., “Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion,” Nature Medicine, vol. 8, no. 8, pp. 793–800, 2002. View at Publisher · View at Google Scholar · View at Scopus
  35. T. Muliaditan, J. W. Opzoomer, J. Caron et al., “Repurposing tin mesoporphyrin as an immune checkpoint inhibitor shows therapeutic efficacy in preclinical models of cancer,” Clinical Cancer Research, vol. 24, no. 7, pp. 1617–1628, 2018. View at Publisher · View at Google Scholar · View at Scopus
  36. P. Sharma and J. P. Allison, “Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential,” Cell, vol. 161, no. 2, pp. 205–214, 2015. View at Publisher · View at Google Scholar · View at Scopus
  37. E. A. Chong, J. J. Melenhorst, S. F. Lacey et al., “PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR,” Blood, vol. 129, no. 8, pp. 1039–1041, 2017. View at Publisher · View at Google Scholar · View at Scopus
  38. K. J. Curran, B. A. Seinstra, Y. Nikhamin et al., “Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression,” Molecular Therapy, vol. 23, no. 4, pp. 769–778, 2015. View at Publisher · View at Google Scholar · View at Scopus
  39. J. Ren, X. Liu, C. Fang, S. Jiang, C. H. June, and Y. Zhao, “Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition,” Clinical Cancer Research, vol. 23, no. 9, pp. 2255–2266, 2017. View at Publisher · View at Google Scholar · View at Scopus