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Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed and/or refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patient’s T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.Chimeric antigen receptor T cells have revolutionized the treatment of patients with certain haematological malignancies. Nonetheless, an optimal approach to lymphodepleting chemotherapy and/or bridging therapies has yet to be defined in patients receiving these agents. In this Review, the authors describe the various lymphodepletion and/or bridging therapy strategies used, and highlight the need for prospective comparisons in order to determine the safest and most effective approach.

Oncolytic viruses (OVs) are an emerging class of cancer therapeutics that offer the benefits of selective replication in tumour cells, delivery of multiple eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumour immunity, and a tolerable safety profile that largely does not overlap with that of other cancer therapeutics. To date, four OVs and one non-oncolytic virus have been approved for the treatment of cancer globally although talimogene laherparepvec (T-VEC) remains the only widely approved therapy. T-VEC is indicated for the treatment of patients with recurrent melanoma after initial surgery and was initially approved in 2015. An expanding body of data on the clinical experience of patients receiving T-VEC is now becoming available as are data from clinical trials of various other OVs in a range of other cancers. Despite increasing research interest, a better understanding of the underlying biology and pharmacology of OVs is needed to enable the full therapeutic potential of these agents in patients with cancer. In this Review, we summarize the available data and provide guidance on optimizing the use of OVs in clinical practice, with a focus on the clinical experience with T-VEC. We describe data on selected novel OVs that are currently in clinical development, either as monotherapies or as part of combination regimens. We also discuss some of the preclinical, clinical and regulatory hurdles that have thus far limited the development of OVs.Oncolytic viruses (OVs) provide a novel cancer treatment strategy, with a mechanism of action and toxicity profiles that are distinctly different to those of more traditional therapies. Thus far, four OVs have entered clinical use globally, yet only talimogene laherparepvec (T-VEC) has entered widespread clinical use. In this Review, the authors describe the clinical and regulatory experience with T-VEC thus far, and how this can guide the development of novel OVs. Discussions of a range of novel OVs with the potential for clinical implementation in the near future are also provided.

Structural imaging remains an essential component of diagnosis, staging and response assessment in patients with cancer; however, as clinicians increasingly seek to noninvasively investigate tumour phenotypes and evaluate functional and molecular responses to therapy, theranostics — the combination of diagnostic imaging with targeted therapy — is becoming more widely implemented. The field of radiotheranostics, which is the focus of this Review, combines molecular imaging (primarily PET and SPECT) with targeted radionuclide therapy, which involves the use of small molecules, peptides and/or antibodies as carriers for therapeutic radionuclides, typically those emitting α-, β- or auger-radiation. The exponential, global expansion of radiotheranostics in oncology stems from its potential to target and eliminate tumour cells with minimal adverse effects, owing to a mechanism of action that differs distinctly from that of most other systemic therapies. Currently, an enormous opportunity exists to expand the number of patients who can benefit from this technology, to address the urgent needs of many thousands of patients across the world. In this Review, we describe the clinical experience with established radiotheranostics as well as novel areas of research and various barriers to progress.Radiotheranostics enables the clinician to image and then target lesions using the same probe. Despite this appealing potential, interest in the field of radiotheranostics has long been constrained by a lack of expertise, high infrastructure costs and the availability of non-radioactive alternative approaches. Nonetheless, several recent successes have led to renewed research interest. In this Review, the authors summarize the current challenges and opportunities in this rapidly emerging area.

Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and continues to portend poor survival, despite multimodal treatment using surgery and chemoradiotherapy. The addition of tumour-treating fields (TTFields)—an approach in which alternating electrical fields exert biophysical force on charged and polarisable molecules known as dipoles—to standard therapy, has been shown to extend survival for patients with newly diagnosed GBM, recurrent GBM and mesothelioma, leading to the clinical approval of this approach by the FDA. TTFields represent a non-invasive anticancer modality consisting of low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz), alternating electric fields delivered via cutaneous transducer arrays configured to provide optimal tumour-site coverage. Although TTFields were initially demonstrated to inhibit cancer cell proliferation by interfering with mitotic apparatus, it is becoming increasingly clear that TTFields show a broad mechanism of action by disrupting a multitude of biological processes, including DNA repair, cell permeability and immunological responses, to elicit therapeutic effects. This review describes advances in our current understanding of the mechanisms by which TTFields mediate anticancer effects. Additionally, we summarise the landscape of TTFields clinical trials across various cancers and consider how emerging preclinical data might inform future clinical applications for TTFields.

The management of advanced-stage renal cell carcinoma (RCC) has been transformed by the development of immune-checkpoint inhibitors (ICIs). Nonetheless, most patients do not derive durable clinical benefit from these agents. Importantly, unlike other immunotherapy-responsive solid tumours, most RCCs have only a moderate mutational burden, and paradoxically, high levels of tumour CD8+ T cell infiltration are associated with a worse prognosis in patients with this disease. Building on the successes of antibodies targeting the PD-1 and CTLA4 immune checkpoints, multiple innovative immunotherapies are now in clinical development for the treatment of patients with RCC, including ICIs with novel targets, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cell therapies and therapeutic vaccines. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a disease-specific framework that incorporates a deep understanding of RCC immunobiology. In this Review, using the structure provided by the well-described cancer–immunity cycle, we outline the key steps required for a successful antitumour immune response in the context of RCC, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyse the most encouraging targets of novel immune-based therapies within the RCC microenvironment, and review the landscape of emerging antigen-directed therapies for this disease.Renal cell carcinomas (RCCs) are generally immunogenic, but only a subset of patients receiving currently approved immune-checkpoint inhibitors have long-term disease remission. In this Review, the authors provide a conceptual framework for developing novel immunotherapy approaches, including an overview of the most promising novel immune checkpoints and antigen-directed therapies, and highlighting the potential of these agents to further improve the outcomes in patients with RCC.

Key Points The routine diagnosis of triple-negative breast cancer (TNBC) depends on the accurate assessment of the status of the oestrogen receptor (ER), progesterone receptor (PgR) and HER2 Chemotherapy remains the standard therapeutic approach for TNBC at all stages, with platinum compounds having a relevant role, especially in patients harbouring BRCA1/2 mutations or 'BRCAness' 'Omics' technologies have provided unprecedented insights into the molecular complexity and heterogeneous clinical behaviour of TNBC but, to date, none of the newly developed molecular classifications has demonstrated clinical utility Several potentially actionable molecular alterations, frequently affecting PI3K/mTOR or RAS/RAF/MEK, have been found in TNBC, but none have been confirmed as a 'driver alteration', nor have any TNBC subsets been shown to be 'addicted' to them Targeted agents currently under clinical investigation in TNBC include PARP inhibitors, PI3K inhibitors, MEK inhibitors, anti-androgen therapies, heat shock protein 90 inhibitors, histone deacetylase inhibitors, and their combinations TNBC is remarkably heterogeneous in terms of the tumour microenvironment; tumour lymphocyte infiltration is associated with good prognosis and a response to chemotherapy, which provides a strong rationale for testing immunotherapies in TNBC Triple-negative breast cancer has a poor outcome compared with other breast cancer subgroups, and chemotherapy is the primary treatment for this disease. 'Omics' technologies have revealed high levels of heterogeneity and helped to identify potentially actionable molecular features in some triple-negative breast cancer subtypes. Proof-of-principle studies suggest a potential benefit from immunotherapy in patients with this disease. Herein, Bianchini et al . discuss the most promising therapeutic opportunities for triple-negative breast cancer. Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.

Exportin 1 (XPO1), also known as chromosome region maintenance protein 1, plays a crucial role in maintaining cellular homeostasis via the regulated export of a range of cargoes, including proteins and several classes of RNAs, from the nucleus to the cytoplasm. Dysregulation of this protein plays a pivotal role in the development of various solid and haematological malignancies. Furthermore, XPO1 is associated with resistance to several standard-of-care therapies, including chemotherapies and targeted therapies, making it an attractive target of novel cancer therapies. Over the years, a number of selective inhibitors of nuclear export have been developed. However, only selinexor has been clinically validated. The novel mechanism of action of XPO1 inhibitors implies a different toxicity profile to that of other agents and has proved challenging in certain settings. Nonetheless, data from clinical trials have led to the approval of the XPO1 inhibitor selinexor (plus dexamethasone) as a fifth-line therapy for patients with multiple myeloma and as a monotherapy for patients with relapsed and/or refractory diffuse large B cell lymphoma. In this Review, we summarize the progress and challenges in the development of nuclear export inhibitors and discuss the potential of emerging combination therapies and biomarkers of response.Nuclear import and export proteins, such as exportin 1(XPO1), regulate the transport of proteins and other molecules into and out of the nucleus, including several tumour suppressor proteins. The dysregulation of nuclear export can be observed in several types of haematological and solid tumours, providing a rationale for a novel form of targeted therapy. In this Review, the authors describe the development of XPO1 inhibitors, from basic research to clinical approval.

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control. Monomethyl auristatin (MMAE), also known for its radiosensitizer properties, is a common antibody drug conjugate used for cancer therapy. Here the authors show that, in combination with radiotherapy, tumor-directed antibodies or peptides conjugated to MMAE promote anti-tumor immune responses, improving response to checkpoint inhibitors in preclinical cancer models.

Owing to improvements in our understanding of the biological principles of tumour initiation and progression, a wide variety of novel targeted therapies have been developed. Developments in biomedical imaging, however, have not kept pace with these improvements and are still mainly designed to determine lesion size alone, which is reflected in the Response Evaluation Criteria in Solid Tumors (RECIST). Imaging approaches currently used for the evaluation of treatment responses in patients with solid tumours, therefore, often fail to detect successful responses to novel targeted agents and might even falsely suggest disease progression, a scenario known as pseudoprogression. The ability to differentiate between responders and nonresponders early in the course of treatment is essential to allowing the early adjustment of treatment regimens. Various imaging approaches targeting a single dedicated tumour feature, as described in the hallmarks of cancer, have been successful in preclinical investigations, and some have been evaluated in pilot clinical trials. However, these approaches have largely not been implemented in clinical practice. In this Review, we describe current biomedical imaging approaches used to monitor responses to treatment in patients receiving novel targeted therapies, including a summary of the most promising future approaches and how these might improve clinical practice.The development of more-targeted cancer therapies has not been matched by more-targeted imaging methods. This discrepancy has, in some scenarios, resulted in inaccurate assessments of the effects of novel therapies. In this Review, the authors describe potential novel imaging approaches that could be adopted to enable improvements in imaging-based monitoring of treatment responses and resistance.

Conventional chemotherapeutics have been developed into clinically useful agents based on their ability to preferentially kill malignant cells, generally owing to their elevated proliferation rate. Nonetheless, the clinical activity of various chemotherapies is now known to involve the stimulation of anticancer immunity either by initiating the release of immunostimulatory molecules from dying cancer cells or by mediating off-target effects on immune cell populations. Understanding the precise immunological mechanisms that underlie the efficacy of chemotherapy has the potential not only to enable the identification of superior biomarkers of response but also to accelerate the development of synergistic combination regimens that enhance the clinical effectiveness of immune checkpoint inhibitors (ICIs) relative to their effectiveness as monotherapies. Indeed, accumulating evidence supports the clinical value of combining appropriately dosed chemotherapies with ICIs. In this Review, we discuss preclinical and clinical data on the immunostimulatory effects of conventional chemotherapeutics in the context of ICI-based immunotherapy.The efficacy of chemotherapy in patients with cancer is now known to have an immunogenic component. Nonetheless, chemotherapy alone often fails to provide durable disease remission in most patients. The development of immune checkpoint inhibitors has created an opportunity to combine immunogenic chemotherapies with these agents in order to optimize patient outcomes. In this Review, the authors describe the mechanisms of synergy between chemotherapy and immune checkpoint inhibitors, summarize the available clinical data on these effects and highlight the most promising areas for future research.