Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

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CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

Bioactive materials are a special class of biomaterials that can react in vivo to induce a biological response or regulate biological functions, thus achieving a better curative effect than traditional inert biomaterials. For cancer theranostics, compared with organic or polymer nanomaterials, inorganic nanomaterials possess unique physical and chemical properties, have stronger mechanical stability on the basis of maintaining certain bioactivity, and are easy to be compounded with various carriers (polymer carriers, biological carriers, etc.), so as to achieve specific antitumor efficacy. After entering the nanoscale, due to the nano-size effect, high specific surface area and special nanostructures, inorganic nanomaterials exhibit unique biological effects, which significantly influence the interaction with biological organisms. Therefore, the research and applications of bioactive inorganic nanomaterials in cancer theranostics have attracted wide attention. In this review, we mainly summarize the recent progress of bioactive inorganic nanomaterials in cancer theranostics, and also introduce the definition, synthesis and modification strategies of bioactive inorganic nanomaterials. Thereafter, the applications of bioactive inorganic nanomaterials in tumor imaging and antitumor therapy, including tumor microenvironment (TME) regulation, catalytic therapy, gas therapy, regulatory cell death and immunotherapy, are discussed. Finally, the biosafety and challenges of bioactive inorganic nanomaterials are also mentioned, and their future development opportunities are prospected. This review highlights the bioapplication of bioactive inorganic nanomaterials.

Bioactive inorganic nanomaterials for cancer theranostics.

Leukemia is a hematological malignancy associated with the uncontrolled proliferation of mutant progenitors, suppressing the production of normal blood cells. Current treatments, including chemotherapy, radiotherapy, and immunotherapy, still lead to unsatisfactory results with a 5 year survival rate of only 30-50%. The poor prognosis is related to both disease relapse and treatment-associated toxicity. Delivery strategies can improve the in vivo pharmacokinetics of drugs, navigating the therapeutics to target cells or the tumor microenvironment and reversing drug resistance, which maximizes tumor elimination and alleviates systematic adverse effects. This review discusses available FDA-approved anti-leukemia drugs and therapies with a focus on the advances in the development of anti-leukemia drug delivery systems. Additionally, challenges in clinical translation of the delivery strategies and future research opportunities in leukemia treatment are also included.

Delivery strategies in treatments of leukemia.

Destroying pathogen-tumor symbionts synergizing with catalytic therapy of colorectal cancer by biomimetic protein-supported single-atom nanozyme

Hematologic malignancies (HMs) pose a serious threat to patients' health and life, and the five-year overall survival of HMs remains low. The lack of understanding of the pathogenesis and the complex clinical symptoms brings immense challenges to the diagnosis and treatment of HMs. Traditional therapeutic strategies for HMs include radiotherapy, chemotherapy, targeted therapy and hematopoietic stem cell transplantation. Although immunotherapy and cell therapy have made considerable progress in the last decade, nearly half of patients still relapse or suffer from drug resistance. Recently, studies have emerged that nanomaterials, nanotechnology and nanomedicine show great promise in cancer therapy by enhancing drug targeting, reducing toxicity and side effects and boosting the immune response to promote durable immunological memory. In this review, we summarized the strategies of recently developed nanomaterials, nanotechnology and nanomedicines against HMs and then proposed emerging strategies for the future designment of nanomedicines to treat HMs based on urgent clinical needs and technological progress. 

/pdf/development-and-application-of-nanomaterials-nanotechnology-3o0rp2cd.pdf

Development and application of nanomaterials, nanotechnology and nanomedicine for treating hematological malignancies

In recent years, the excellent curative effect of CD19-specific chimeric antigen receptor (CAR) T-cell therapy has brought hope to patients with relapsing or refractory B-cell hematological malignancies, however relapse after CAR T-cell infusion has hindered the widespread clinical application of this immunotherapy and targeted antigen-negative relapse has caused widespread concern. Consequently, strategies for increasing targeted antigens have been created. In addition to the most widely applied target, namely CD19, researchers have further explored the possibility of other targets, such as CD20, CD22, CD33, and CD123, and have tested a series of combination antigen CAR T-cell therapies. Here, we summarize the current preclinical and clinical studies of dual-target CAR T cells.

Preclinical and clinical advances in dual-target chimeric antigen receptor therapy for hematological malignancies

Trivalent arsenic (AsIII) is an effective agent for treating patients with acute promyelocytic leukaemia, but its ionic nature leads to several major limitations like low effective concentrations in leukaemia cells and substantial off-target cytotoxicity, which limits its general application to other types of leukaemia. Here, building from our clinical discovery that cancerous cells from patients with different leukaemia forms featured stable and strong expression of CD71, we designed a ferritin-based As nanomedicine, As@Fn, that bound to leukaemia cells with very high affinity, and efficiently delivered cytotoxic AsIII into a large diversity of leukaemia cell lines and patient cells. Moreover, As@Fn exerted strong anti-leukaemia effects in diverse cell-line-derived xenograft models, as well as in a patient-derived xenograft model, in which it consistently outperformed the gold standard, showing its potential as a precision treatment for a variety of leukaemias. Trivalent arsenic (AsIII) is a clinically approved treatment agent for patients with promyelocytic leukaemia, but cannot be used for other types of leukaemia due to its toxicity. Here the authors show that different patient-derived leukaemia cells express CD71 and design a ferritin-based nanoparticle for specific delivery of AsIII to these cells, demonstrating substantially improved efficacy towards different leukaemia types in animal models, with reduced side effects.

Ferritin-based targeted delivery of arsenic to diverse leukaemia types confers strong anti-leukaemia therapeutic effects

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Preclinical and clinical advances in dual-target chimeric antigen receptor therapy for hematological malignancies

Ferritin-based targeted delivery of arsenic to diverse leukaemia types confers strong anti-leukaemia therapeutic effects