Cancer immunotherapies

Intratumourally administered bacteria coated with manganese dioxide modulate the immunosuppressive tumour microenvironment and potently activate antitumour immune responses, as shown in multiple solid tumours in small animals.

The intravenous injection of neutrophils bearing discoidal polymer microscale ‘patches’ on their surfaces reduces tumour burden in mice owing to the patch-induced polarization of the neutrophils towards an antitumour phenotype.

The off-tumour toxicity of a supramolecular bispecific T cell engager can be halted by disengaging T cells from the tumour cells via the disassembly of the supramolecular aggregate through the infusion of the small-molecule drug amantadine.

Replacing the extracellular domains of heterodimeric cytokine receptors in chimeric antigen receptor T cells with two leucine zipper motifs leads to optimal JAK/STAT signalling and augments the effector function of the T cells.

A subcutaneously injected hydrogel conjugated with antibodies for interleukin-6 substantially reduces the levels of the cytokine during chimaeric antigen receptor T-cell therapy while maintaining its antitumour efficacy.

A cell-barcoding method leveraging ubiquitous promoters to express small-RNA barcodes modified with direct-capture sequences allows for the longitudinal tracking of the transcriptional states of CAR T cells infused in a mouse model of leukaemia.

T cells with a chimaeric antigen receptor specific for fluorescein isothiocyanate can be directed against solid tumours via the intratumoural administration of a fluorescein isothiocyanate-conjugated amphiphile that inserts itself in cell membranes.

Durable anti-tumour responses can be triggered by maximizing the cooperative phagocytic potency of macrophages through the disruption of the CD47–SIRPα macrophage checkpoint and by delivering a tumour-opsonizing monoclonal antibody.

Potent circulating tumour-reactive lymphocytes can be isolated from peripheral blood at high yield and purity via microfluidic immunomagnetic cell sorting.

The spatial distribution and placement of antigens in nanoparticle-based cancer vaccines can substantially affect antigen processing, cytokine production, the induction of immune memory and tumour growth.

Intra-tumourally injected hollow nanoparticles displaying the polysaccharide mannan downregulate the fraction of regulatory T cells in the tumour microenvironment and induce anti-tumour responses mediated by T helper 17 cells.

Cytotoxic CAR T cells derived from human induced pluripotent stem cells can be genetically engineered for enhanced proliferation and persistency in solid tumours.

An anti-CD98 antibody with pH-dependent binding elicits tumour-specific Fc-mediated anti-tumour activity in multiple xenograft and syngeneic tumour models established in CD98-humanized mice.

Potent allogeneic CD8αβ⁺ CAR T cells devoid of alloreactive potential can be generated from human T-cell-derived induced pluripotent stem cells via the timed and calibrated expression of a CAR that substitutes for the T-cell receptor.

Screening a large barcoded library of unique CD19-specific chimaeric antigen receptors with diverse intracellular domains allows for the discovery of receptors that elicit enhanced antitumoural functions.

Synthetically generated and clonally expanded libraries of immune cells displaying diverse repertoires of chimaeric antigen receptors lead to long-lasting and potent antitumour responses in mouse models of epithelial tumours.

Masking interleukin-12 with a domain of the interleukin-12 receptor via a linker cleavable by tumour-associated proteases eliminates systemic immune-related adverse events and triggers potent therapeutic effects in mice bearing immunologically cold tumours.

Tumour vaccines consisting of outer membrane vesicles bearing a specific tumour antigen and produced in the intestine by ingested genetically engineered bacteria generate long-term antitumour immunity in mice.

T cells expressing a pluripotent pro-inflammatory neutrophil-activating protein from Helicobacter pylori trigger endogenous bystander T-cell responses against solid cancers.

Potent chimaeric antigen receptor T cells can be generated within one day from T cells derived from peripheral blood without the need for T-cell activation.

A nanoscale metal–organic framework that modulates the immunological and mechanical properties of the tumour microenvironment enhances the outcomes of radiotherapy–radiodynamic therapy, especially when combined with checkpoint blockade.

Flagellated bacteria coated with antigen-adsorbing polymer nanoparticles and injected into tumours in mice after radiotherapy elicit systemic antitumour effects by transporting antigens to the tumour’s periphery.

The intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide leads to weeks-long retention of the cytokines in the tumours with minimal side effects, as shown in multiple syngeneic mouse models.

Cancer cells enriched in cholesterol in their plasma membrane impair T-cell-mediated cytotoxicity, which can be augmented by stiffening the cancer cells via cholesterol depletion, as shown in mouse models of adoptive T-cell immunotherapy.

Antitumour immune responses to checkpoint blockade can be augmented by modulating the microbiota in the tumour with hydrogel-embedded silver nanoparticles and specific exogenous bacteria, as shown for mice with squamous carcinoma tumours.

Epigenetic inhibitors that promote antigen presentation and potentiate T-cell-mediated cytotoxicity can be identified by a high-throughput screen of cytotoxic T-cell activity in breast tumour organoids.

A bispecific antibody targeting the T-cell co-receptor CD3ε and the immune checkpoint programmed-death ligand 1 on dendritic cells rejuvenates tumour-specific CD8 T cells, leading to durable antitumour responses in murine models of cancer.

The concurrent depletion of tumour cells and immunosuppressive cells via a monoclonal antibody targeting a common surface marker prevents tumours from acquiring resistance to therapies involving immune checkpoint blockade.

Efficacious cancer vaccines can be made via the cryogenic silicification of tumour cells followed by the decoration of the silicified surface with pathogen-associated molecular patterns.

Monoclonal antibodies conjugated with multiple polymer chains functionalized to target glucose transporter 1 and detaching in the reductive tumour microenvironment augment the potency and safety of checkpoint blockade therapy for glioblastoma.

Spatial control of the production of immunomodulatory biologics by CAR T cells engineered with synthetic gene switches that respond to mild elevations in temperature enhances the cells’ antitumour activity.

The activity of engineered T cells within tumours can be controlled via the heat generated by pulses of focused ultrasound by modifying the cells to express a chimeric antigen receptor under the control of a promoter for the heat-shock protein.

Human natural killer cells with potent anticancer activity can be directly reprogrammed from somatic cells using pluripotency transcription factors and an optimized reprogramming medium.

An orally administered gel that is retained in the colon modulates the gut microbiome of mice with murine tumours, inducing systemic memory-T-cell responses and amplifying the antitumour activity of a checkpoint inhibitor.

Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.

T cells derived from human induced pluripotent stem cells lacking certain components of the human leukocyte antigen system and incorporating a ligand that inhibits natural killer cells escape rejection when implanted in allogeneic mice.

A mathematical model of the time course of tumour responses to immunotherapy predicts tumour burden and treatment sensitivity across cancer types and drug combinations.

CAR-T cells specific for a neoantigen derived from the driver oncogene nucleophosmin display potent and specific cytotoxic activity in mouse models of human acute myeloid leukaemia.

A collagen-binding interleukin-12 formulation intravenously injected into mice bearing established immunologically cold mouse tumours led to marked tumour remission, particularly when combined with checkpoint-inhibitor immunotherapy.

This Perspective outlines the current map and known functions of populations of tumour-infiltrating myeloid cells in cancer, and discusses their implications for cancer therapy and biological research.

This Perspective overviews immunotherapies leveraging engineering approaches, including the design of biomaterials, delivery strategies and nanotechnology solutions, for the realization of individualized cancer treatments.

DNA aptamers that specifically bind to the T-cell marker CD8 and can be displaced by a complementary oligonucleotide enable the isolation, at high purity and yield, of CD8⁺ T cells for chimeric antigen receptor T-cell therapies.

The physiological degradation of programmed-death ligand 1 is reduced by the palmitoylation of its intracellular domain, and this process can be inhibited to promote T-cell immunity against tumours.

The systemic administration of haematopoietic stem cells conjugated to anti-PD-1-decorated platelets in leukaemic mice promotes the delivery of the checkpoint inhibitor to the bone marrow and suppresses the growth and recurrence of leukaemia.

The combination of systemic immune checkpoint inhibition with local administration of a hydrogel containing the enzyme catalase, a radioisotope and an immunostimulatory agent promotes effective antitumour immune responses in mice models.

A supramolecule that inhibits the colony stimulating factor 1 and SIRPα receptors on macrophages significantly enhances antitumour and antimetastatic efficacies in two aggressive animal models of melanoma and breast cancer.

This Review discusses the manufacturing of cell products for clinically advanced cell therapies, and highlights potential manufacturing bottlenecks and solutions towards the cost-effective commercialization of the therapies.

β-Cyclodextrin nanoparticles carrying an antagonist of the toll-like receptors TLR7 and TLR8 drive the M1 phenotype in tumour-associated macrophages and improve immunotherapy response rates in tumour mouse models when used with checkpoint blockade.

This Review Article provides an overview of chimeric antigen receptors (CARs) for T cells and discusses engineering strategies for the design of next-generation CAR-T therapies for haematologic and solid cancers.

Combining immune checkpoint inhibition with radiotherapy–radiodynamic therapy, enabled by intratumorally injected nanoscale metal–organic frameworks, promotes systemic antitumour immunity and tumour rejection in mouse models of breast and colorectal cancer.

This Perspective discusses recent technological developments in flow cytometry and DNA sequencing that enable the interrogation of T-cell specificities in infection, cancer and autoimmunity to inform disease development and treatment.

Drawing from recent successes in cancer immunotherapy, this Perspective discusses that effective cancer-nanomedicine therapies can be designed to prime antitumour immunity far from the site of disease.

By targeting the surgical bed and circulating tumour cells, platelets conjugated with an antibody against an immune checkpoint protein prevent tumour recurrence and metastasis following resection of the primary tumour.

Disrupting the CD47–SIRPα checkpoint in tumour macrophages and delivering a tumour-opsonizing monoclonal antibody maximizes the macrophages’ cooperative phagocytic potency.

Antitumour responses mediated by T helper 17 cells can be induced by intratumourally injected hollow nanoparticles displaying the polysaccharide mannan.

Flagellated bacteria coated with antigen-adsorbing nanoparticles and injected into irradiated tumours elicit systemic antitumour immune responses by transporting tumour antigens towards the tumour periphery, where they are taken up by functional antigen-presenting cells.

The repertoire of new preclinical strategies for fighting tumours that resist or evade immunotherapy drugs and cellular immunotherapies is widening.

The efficacy of adoptive cell therapy for pancreatic cancer can be augmented by antigen-specific cytotoxic T cells genetically engineered to overexpress a C-X-C chemokine receptor whose ligand is highly expressed by pancreatic cancer cells.

The effectiveness of cancer immunotherapies will benefit from a range of strategies — new, or borrowed from other classes of therapeutic — to trigger durable immune responses.

The restoration of a local chemokine gradient by nanoparticles non-covalently anchored on the surface of systemically administered red blood cells delays cancer progression in mouse models of lung metastasis.

The phagocytic clearance of the large fraction of transplanted cells that typically undergo rapid cell death contributes to therapeutic outcomes.

The time course of tumour responses to immunotherapies can be mathematically predicted on the basis of tumour-growth rates, the rates of immune activation and of tumour–immune-cell interactions, and the efficacy of immune-mediated tumour killing.

The intravenous administration of a formulation of interleukin-12 that binds to collagen in established ‘immunologically cold’ murine tumours enhances interferon-γ production by T cells and causes tumour remission, especially when in combination with immune checkpoint blockade therapy.

The overexpression of the transcription factor c-Jun improves chimeric-antigen-receptor T-cell functionality and enhances the killing of low-antigen-expressing liquid and solid cancers in mice.

Broadening access to personalized medicines will require scalable and efficient manufacturing processes that help decrease production costs.

In mouse models of cancer, the inhibition of a set of regulatory proteins improves checkpoint-blockade therapy by causing regulatory T cells to produce the cytokine interferon-γ.

In the manufacturing of cell-based therapeutics, isolating cells via DNA aptamers is an attractive alternative to magnetic-activated cell sorting.

Autoimmune diseases should benefit from treatments that piggyback on the successes of cancer immunotherapies.

Enhanced lysosomal degradation of the transmembrane protein programmed cell-death protein-1 ligand in tumour cells, enabled by blocking the protein’s post-translational lipid modification, promotes T-cell-mediated suppression of tumour growth in mice.

Immunotherapies developed to treat cancer can be adapted to treat autoimmunity.

The coupling of blood platelets bearing anti-programmed cell death protein 1 antibodies to haematopoietic stem cells enables delivery of checkpoint-blockade therapy to bone marrow to promote T-cell-mediated control of leukaemia in mice.

Cancer therapies that target multiple biological pathways take advantage of synergistic killing, and decrease the risk of relapse.

Intratumoral injection of a hydrogel impregnated with radioisotope-labelled catalase and an immunostimulant, along with systemic immune checkpoint blockade, inhibits tumour growth in mouse models of localized cancer and metastatic cancer.

Two drug-loaded nanoparticle formulations that preferentially accumulate within tumour-associated macrophages induce macrophage repolarization to a tumoricidal state that leads to potent antitumour activity in multiple murine models of cancer.

Bringing truly personalized cancer vaccination with tumour neoantigens to the clinic will require overcoming the challenges of optimized vaccine design, manufacturing and affordability, and identification of the most suitable clinical setting.

Nanoscale metal–organic frameworks carrying an immunotherapy payload and administered into tumours alongside a low dose of radiotherapy enhance local and systemic antitumour immunity in mouse models of breast cancer and colorectal cancer.

For cell therapies to transition from promises to products, increased efforts need to be put into the identification of the factors and biological mechanisms that affect safety and efficacy, and into the design of cost-effective methods for the harvesting, expansion, manipulation and purification of the cells.

Potent dendritic-cell cancer vaccines could be used to induce functional antitumour immunity without off-target toxicity.

A vaccine based on induced pluripotent stem cells mimicking the expression of tumour-cell antigens induces significant antitumour immune responses in mouse models.

T cells can be efficiently and controllably expanded for adoptive cell therapy in a culture system consisting of lipid bilayers bearing membrane-bound cues for the stimulation of T-cell receptors and of supporting silica microrods that release a T-cell proliferation factor.

Platelets delivering the immunotherapeutic antibody anti-PD-L1 to the site of surgically removed tumours reduce cancer recurrence and metastatic spread in mice.