Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment

Chimeric antigen receptor （CAR） is a recombinant immunoreceptor combining an antibody-derived target- ing fragment with signaling domains capable of acti- vating cells, which endows T cells with the ability to recognize tumor-associated surface antigens indepen- dent of the expression of major histocompatibiiity complex （MHC） molecules. Recent early-phase clinical trials of CAR-modified T （CAR-T） cells for relapsed or refractory B cell malignancies have demonstrated promising results （that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia （B-ALL））. Given this suc- cess, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation.

Spotlight on chimeric antigen receptor engineered T cell research and clinical trials in China

T cell mediated adoptive immune response has been characterized as the key to anti-tumor immunity. Scientists around the world including in China, have been trying to harness the power of T cells against tumors for decades. Recently, the biosynthetic chimeric antigen receptor engineered T cell(CAR-T) strategy was developed and exhibited encouraging clinical efficacy, especially in hematological malignancies. Chimeric antigen receptor research reports began in 2009 in China according to our Pub Med search results. Clinical trials have been ongoing in China since 2013 according to the trial registrations on clinicaltrials.gov.. After years of assiduous efforts, research and clinical scientists in China have made their own achievements in the CAR-T therapy field. In this review, we aim to highlight CAR-T research and clinical trials in China, to provide an informative reference for colleagues in the field.

Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo

Human epidermal growth factor receptor 2 （HER2） pro- teins are overexpressed in a high proportion of gastric cancer （GC） cases and affect the maintenance of cancer stem cell （CSC） subpopulations, which are used as tar- gets for the clinical treatment of patients with HER2- positive GC. Despite improvements in survival, numer- ous HER2-positive patients fail treatment with trastuzu- mab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor （CAR）, and targeting the GC cell antigen HER2, which harbors the CD137 and CD3/; moieties. Our findings show that the expanded CART cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-in- dependent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CART cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing totargets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.

An analytical biomarker for treatment of patients with recurrent B-ALL after remission induced by infusion of anti-CD19 chimeric antigen receptor T(CAR-T) cells

Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune-cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines(mainly interleukin 6 and C-reactive protein) were identified in two patients(Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.

Targeting cancer stem cells by using chimeric antigen receptor-modified T cells： a potential and curable approach for cancer treatment

Cancer stem cells （CSCs）, a subpopulation of tumor cells, have self-renewal and multi-lineage differentiation abilities that play an important role in cancer initiation, mainte- nance, and metastasis. An accumulation of evidence indicates that CSCs can cause conventional therapy fail- ure and cancer recurrence because of their treatment resistance and self-regeneration characteristics. There- fore, approaches that specifically and efficiently eliminate CSCs to achieve a durable clinical response are urgently needed. Currently, treatments with chimeric antigen receptor-modified T （CART） cells have shown successful clinical outcomes in patients with hematologic malignan- cies, and their safety and feasibility in solid tumors was confirmed. In this review, we will discuss in detail the possibility that CART cells inhibit CSCs by specifically targeting their cell surface markers, which will ultimately improve the clinical response for patients with various types of cancer. A number of viewpoints were summarized to promote the application of CSC-targeted CART cells in clinical cancer treatment. This review covers the key aspects of CSC-targeted CART cells against cancers in accordance with the premise of the model, from bench to bedside and back to bench.

Adaptive T cell immunotherapy in cancer

Impaired tumor-specific effector T cells contribute to tumor progression and unfavorable clinical outcomes. As a compensatoryT cell-dependent cancer immunoediting strategy, adoptive T cell therapy (ACT) has achieved encouraging therapeutic results,and this strategy is now on the center stage of cancer treatment and research. ACT involves the ex vivo stimulation and expansionof tumor-infiltrating lymphocytes (TILs) with inherent tumor reactivity or T cells that have been genetically modified to expressthe cognate chimeric antigen receptor or T cell receptor (CAR/TCR), followed by the passive transfer of these cells into alymphodepleted host. Primed T cells must provide highly efficient and long-lasting immune defense against transformed cellsduring ACT. Anin-depth understanding of the basic mechanisms of these living drugs can help us improve upon currentstrategies and design better next-generation T cell-based immunotherapies. From this perspective, we provide an overview ofcurrent developments in different ACT strategies, with a focus on frontier clinical trials that offer a proof of principle. Meanwhile,insights into the determinants of ACT are discussed, which will lead to more rational, potent and widespread applicationsin the future.

Innovative and propagable translational research model established for cell-based therapy at Chinese PLA General Hospital

The use of translational medicine in Chinese hospitals appears to have become easier over the last decade.Products developed in the laboratory can sometimes be applied in the clinic under life-saving circumstances.Arteannuin is one of the most successful examples of translation during the

Chinese expert consensus on the management of chimeric antigen receptor T cell therapy-associated coagulopathy

Chimeric antigen receptor T-cell(CAR-T)therapy has greatly improved the disease remission rate and long-term survival rate of patients with relapsed/refractory hematological malignancies.[1-3]Currently,several commercial CAR-T products are available in the market and numerous CAR-T clinical trials have been conducted.Attention should be paid to the safety of CAR-T therapy.The main adverse effects of CAR-T therapy are cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS).[4]

Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system

Chimeric antigen receptor(CAR)T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies.However,CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence,in addition to antigen-negative relapse and an immunosuppressive microenvironment.Various preclinical studies are exploring strategies to overcome the above challenges.Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors.In this review,we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies,especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response.We also explored the sensitizing effects of conventional treatment approaches,such as chemotherapy and radiotherapy,on CAR T cell therapy.Finally,we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.