Highlight The emergence of CAR-T cell therapy with its exciting results attained in patients with relapsed and refractory hematological malignancies is considered as the biggest advance in cellular cancer immunotherapy. However, severe side effects and toxicity stir concerns regarding the safety of CAR-T cell treatments.Most of CAR-T cell therapies are currently autologous small-scale treatments for patients suffering from B cell malignancies due to the safety concerns about the potential development of a GVHD in allogeneic therapies. So, allogeneic therapies have been less effective than autologous ones. High cost and highly variable manufacturing processes are other limitations on the way of CAR-T cell therapy. In contrast to the unprecedented responses achieved through using CD19-CAR-T cells in the treatment of ALL, this type of treatment has not shown the same results in the battle against solid tumors that is partly related to different characteristics and microenvironment of solid tumors that limit the success of CAR-T cell therapies in patients with solid tumors. Immune checkpoint therapies with previously reported reproducible beneficial effects in 20–30% of patients with different incurable cancers have serious side effects and considerable cost of repeated administration. Also, recently most patients have not responded effectively to these therapies. In contrast, CAR-T cell therapy has two characteristics that may compensate for the limitations of immune checkpoint therapies. Firstly, only one administration of the engineered T cells is needed for long lasting effectiveness of the therapy. Secondly, more than 90% of patients suffering from ALL respond to CAR-T cell therapy, a result which is not obtained through administration of the immune checkpoints. Future development of CAR-T cell technology should address concerns related to the safety of the treatment and improve toxicity management. Also, it should extend the application of technology in diseases where its effectiveness has been demonstrated and opt for more targets and cancers.

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Abnormal cell differentiation, in particular suppression of terminal cell differentiation, exists in all tumors. Therapeutic interventions to restore terminal differentiation ("differentiation therapy") are a very attractive way to treat cancer, especially leukemia. A variety of chemicals stimulates differentiation of leukemic cells, such as dimethyl sulfoxide (DMSO) and all-trans retinoic acid (ATRA). Tumor suppressor genes have a vital role in the gateway to terminal cell differentiation. In this study, we inhibited PTEN tumor suppressor gene expression by siRNA to investigate the effect of potentiating cell survival and inhibiting apoptosis on HL-60 cell differentiation by DMSO and ATRA. Our results show that PTEN siRNA increases HL-60 cell differentiation in the presence of DMSO and ATRA. At the same time, the presence of siRNA hampers accumulation of apoptotic cells during incubation. Our study suggests that manipulation of PTEN could hold promise for enhancing efficacy of differentiation therapy of acute myelogenous leukemia.