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Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies, but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells 1 . Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells, as witnessed in the past decade by the revolution of clinical practice for B cell malignancies 2 . However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells, resulting in a fragmented therapy landscape with high development costs 2 – 5 . Here we demonstrate that an antibody–drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enables the antigen-specific depletion of the entire haematopoietic system, including HSCs. Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukaemic cells with preserved haematopoiesis. The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased haematopoietic system, irrespective of disease aetiology or originating cell type. We propose that this approach could have broad implications beyond haematological malignancies. An antibody–drug conjugate that targets the pan-haematopoietic marker CD45 combined with transplanted stem cells engineered to be shielded from it can eradicate leukaemic cells while preserving haematopoiesis.

Immunocompromised patients can experience significant morbidity and occasional mortality from complications associated with herpes zoster (HZ), but live attenuated HZ vaccine is contraindicated for these patients. Inactivated zoster vaccine (ZVIN) is in development for prevention of HZ in immunocompromised patients. However, there are limited data in the literature regarding the effect of anti-CD20 monoclonal antibodies on vaccine-related cell-mediated immune response. This study evaluated safety and immunogenicity of ZVIN in patients with hematologic malignancies (HM) receiving anti-CD20 monoclonal antibodies (alone or in combination chemotherapy regimens) and not likely to undergo hematopoietic cell transplant (HCT) (n=80). This was an open-label, single-arm, multicenter Phase I study (NCT01460719) of a 4-dose ZVIN regimen (∼30days between doses) in patients ⩾18years old. Blood samples were collected prior to dose 1 and 28days Postdose 4 to measure varicella zoster virus (VZV)-specific T-cell responses using interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT). The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses at ∼28days Postdose 4, with a geometric fold rise (GMFR) >1.0. All vaccinated patients were evaluated for adverse events (AE) through 28days Postdose 4. ZVIN elicited a statistically significant VZV-specific immune response measured by IFN-γ ELISPOT at 28days Postdose 4 (GMFR=4.34 [90% CI:3.01, 6.24], p-value<0.001), meeting the pre-specified success criterion. Overall, 85% (68/80) of patients reported ⩾1 AE, 44% (35/80) reported ⩾1 injection-site AE, and 74% (59/80) reported ⩾1 systemic AE. The majority of systemic AEs were non-serious and considered unrelated to vaccination by the investigator. Frequencies of AEs did not increase with subsequent doses of vaccine. No recipient of ZVIN had rash polymerase chain reaction (PCR) positive for VZV vaccine strain. In adults with HM receiving anti-CD20 monoclonal antibodies, ZVIN was well-tolerated and elicited statistically significant VZV-specific T-cell responses ∼28days Postdose 4. CLINICALTRIALS.GOV identifier: NCT01460719.

The time to neutrophil engraftment for adult patients after myeloablative double unit umbilical cord blood (UCB) transplantation is 23 days when the two units are given i.v. We hypothesized that the intra-BM injection (IBMI) of one of the two UCB units would reduce systemic loss of hematopoietic progenitors and shorten time to neutrophil recovery after myeloablation. Ten patients with a median age of 35 years were transplanted. The unit to be given by IBMI was randomly assigned; the other unit was given i.v. The median infused graft total nucleated cell dose was 3.7 × 10 7 /kg with no difference between i.v. and IBMI units. All patients tolerated the procedure well, and there was no severe adverse event related to IBMI. The median time to neutrophil engraftment and plt recovery >50 000/μl was 21 and 69 days, respectively. In all, 9 of 10 patients engrafted, 5 with the i.v. unit and 4 with the IBMI unit; 7 of 8 evaluable patients developed acute GVHD and 5 of 10 patients died from treatment-related causes. Survival was 47% at 1 year. Despite safety of administration, IBMI of one of two UCB units did not shorten the time to neutrophil engraftment and offers no advantage over conventional double unit transplantation.

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several haematological malignancies and is being investigated in patients with various solid tumours. Characteristic CAR T cell-associated toxicities such as cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now well-recognized, and improved supportive care and management with immunosuppressive agents has made CAR T cell therapy safer and more feasible than it was when the first regulatory approvals of such treatments were granted in 2017. The increasing clinical experience with these therapies has also improved recognition of previously less well-defined toxicities, including movement disorders, immune effector cell-associated haematotoxicity (ICAHT) and immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as the substantial risk of infection in patients with persistent CAR T cell-induced B cell aplasia and hypogammaglobulinaemia. A more diverse selection of immunosuppressive and supportive-care pharmacotherapies is now being utilized for toxicity management, yet no universal algorithm for their application exists. As CAR T cell products targeting new antigens are developed, additional toxicities involving damage to non-malignant tissues expressing the target antigen are a potential hurdle. Continued prospective evaluation of toxicity management strategies and the design of less-toxic CAR T cell products are both crucial for ongoing success in this field. In this Review, we discuss the evolving understanding and clinical management of CAR T cell-associated toxicities.Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of various haematological malignancies but is associated with characteristic toxicities as well as less well-defined adverse effects, many of which can be severe and potentially fatal. The increasing clinical experience with CAR T cell products has resulted in better recognition and management of these toxicities using a range of pharmacotherapies, although this is an area of continued evolution and refinement. In this Review, Brudno and Kochenderfer discuss the current understanding and clinical management of CAR T cell-associated toxicities.

Engineering a patient’s own T cells to selectively target and eliminate tumour cells has cured patients with untreatable haematologic cancers. These results have energized the field to apply chimaeric antigen receptor (CAR) T therapy throughout oncology. However, evidence from clinical and preclinical studies underscores the potential of CAR T therapy beyond oncology in treating autoimmunity, chronic infections, cardiac fibrosis, senescence-associated disease and other conditions. Concurrently, the deployment of new technologies and platforms provides further opportunity for the application of CAR T therapy to noncancerous pathologies. Here we review the rationale behind CAR T therapy, current challenges faced in oncology, a synopsis of preliminary reports in noncancerous diseases, and a discussion of relevant emerging technologies. We examine potential applications for this therapy in a wide range of contexts. Last, we highlight concerns regarding specificity and safety and outline the path forward for CAR T therapy beyond cancer. The rationale behind chimaeric antigen receptor T cell therapy is reviewed, and current challenges in oncology, preliminary reports in noncancerous diseases and relevant emerging technologies are discussed.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses. A study of hospitalized patients infected with SARS-CoV-2 and who have liquid or solid cancer suggests that hematologic malignancy is an independent risk factor for mortality and that CD8 + T cells might limit infection in this setting irrespective of humoral immunity.

Key Points Adoptive immunotherapy has rapidly evolved to harness modern genetic techniques to create T cells with enhanced specificity, efficacy and safety. Artificial expression of chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) in autologous T cells has enabled a new generation of targeted cellular therapeutics. Early clinical trials targeting B cell malignancies have shown great promise, generating unprecedented response rates to treatment of patients with relapsed and refractory B cell acute lymphoblastic leukaemia (B-ALL). As more patients with different B cell malignancies are treated, areas for further optimization are brought to light. Engineered T cell therapy has been adapted to treat non-B cell malignancies, including multiple myeloma and myeloid malignancies as well as solid tumours. To date, target selection has proved challenging as many tumour-conserved markers are also expressed on benign tissues (for example, mesothelin) and other tumour-specific markers are less uniformly expressed (for example, epidermal growth factor receptor variant III (EGFRvIII)). More precise targeting of tumour cell subsets, such as cancer stem cells, or targeting of portions of intracellular tumour markers in the context of the major histocompatibility complex (MHC), may enhance specificity and limit off-tumour effects. Combining non-specific and specific immune responses (for example, T cells redirected for universal cytokine killing (TRUCKs), fluorescein isothiocyanate (FITC)–folate plus FITC-CAR T cell) could further enhance antitumour immune response, while minimizing off-tumour effects. Although lentiviral and retroviral transduction are still the most common approaches to ex vivo T cell gene modification, DNA and RNA transfection have some advantages. In particular, RNA transfection of short guide RNAs enables CRISPR–Cas9 modification of T cells. This targeted gene disruption approach could help to create engineered T cells with supraphysiological antitumour capabilities. In addition to specificity-enhancing artificial receptor expression, the next generation of engineered T cells may include modifications to overcome tumour-mediated immune suppression, additional receptors to enable Boolean gating of signal transduction or safety switches to enhance precision control of in vivo engineered T cell activity. This Review assesses what we have learnt about adoptive cell transfer of engineered T cells for the treatment of patients with B cell malignancies and discusses how this therapy can be improved and applied to other malignancies, including solid tumours. The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy. Recent clinical trials using T cells engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have produced stunning results in patients with relapsed or refractory haematological malignancies. In this Review we describe some of the most recent and promising advances in engineered T cell therapy with a particular emphasis on what the next generation of T cell therapy is likely to entail.

Crystal Mackall and colleagues report that antigen-independent signaling of chimeric antigen receptors (CARs) causes T cell exhaustion and reduced therapeutic efficacy of CAR T cells that can be overcome by incorporating the 4-1BB costimulatory domain into the CAR. Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy. Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials.

DNA methylation inhibitors have become the mainstay for treatment of certain haematological malignancies. In addition to their abilities to reactivate genes, including tumour suppressors, that have acquired DNA methylation during carcinogenesis, they induce the expression of thousands of transposable elements including endogenous retroviruses and latent cancer testis antigens normally silenced by DNA methylation in most somatic cells. This results in a state of viral mimicry in which treated cells mount an innate immune response by turning on viral defence genes and potentially expressing neoantigens. Furthermore, these changes mediated by DNA methylation inhibitors can also alter the function of immune cells relevant to acquired immunity. Additionally, other inhibitors of epigenetic processes, such as histone deacetylases, methylases and demethylases, can elicit similar effects either individually or in combinations with DNA methylation inhibitors. These findings together with rapid development of immunotherapies open new avenues for cancer treatment.In this Review, Jones et al. present the evidence that epigenetic therapies can induce the expression of endogenous retroviruses and cancer–testis antigens normally silenced by DNA methylation in most somatic cells. As a consequence, a state of viral mimicry is evoked in cancer cells, leading to an innate immune response. Understanding this process has implications for combination therapy with epigenetic drugs and immunotherapies to improve clinical outcomes for patients with cancer.