As Nature Communications celebrates a 10-year anniversary, the field has witnessed the transition of cancer immunotherapy from a pipe dream to an established powerful cancer treatment modality. Here ...we discuss the opportunities and challenges for the future.
Chimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia (AML) has thus far been elusive, in part owing to the absence of truly AML-specific surface antigens, making AML difficult to ...target. However, progress has been made toward the use of CAR T-cell therapy in this disease, prompting the topic of this paper. Discussion and clinical examples of potential solutions to creating a safe and effective CAR T cell for AML include: (1) Decreasing the potency or activity of CAR T cells to enhance the therapeutic window; (2) Using transient or depletable CAR T cells as part of pre-transplant conditioning; and (3) Using a gene-edited allogeneic donor hematopoietic stem cell transplant in order to allow safe and protracted anti-AML CAR T-cell function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers
. However, little is known about the long-term potential and ...clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia
who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4
population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4
CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8
CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In religious philosophy, the concept of karma represents the effect of one's past and present actions on one's future. Macrophages are highly plastic cells with myriad roles in health and disease. In ...the setting of cancer, macrophages are among the most plentiful members of the immune microenvironment where they generally support tumor growth and restrain antitumor immunity. However, macrophages are not necessarily born bad. Macrophages or their immediate progenitors, monocytes, are induced to traffic to the tumor microenvironment (TME) and during this process they are polarized toward a tumor-promoting phenotype. Efforts to deplete or repolarize tumor-associated macrophages (TAM) for therapeutic benefit in cancer have to date disappointed. By contrast, genetic engineering of macrophages followed by their transit into the TME may allow these impressionable cells to mend their ways. In this review, we summarize and discuss recent advances in the genetic engineering of macrophages for the treatment of cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Chimaeric antigen receptor (CAR) T cells can generate durable clinical responses in B-cell haematologic malignancies. The manufacturing of these T cells typically involves their activation, followed ...by viral transduction and expansion ex vivo for at least 6 days. However, the activation and expansion of CAR T cells leads to their progressive differentiation and the associated loss of anti-leukaemic activity. Here we show that functional CAR T cells can be generated within 24 hours from T cells derived from peripheral blood without the need for T-cell activation or ex vivo expansion, and that the efficiency of viral transduction in this process is substantially influenced by the formulation of the medium and the surface area-to-volume ratio of the culture vessel. In mouse xenograft models of human leukaemias, the rapidly generated non-activated CAR T cells exhibited higher anti-leukaemic in vivo activity per cell than the corresponding activated CAR T cells produced using the standard protocol. The rapid manufacturing of CAR T cells may reduce production costs and broaden their applicability.
•Gene editing using CRIPSR/Cas has the potential to increase anti-tumor efficacy and persistence of adoptively transferred cells.•Allogeneic T cells can be made safer and more effective using ...multiplex genome editing and are already in the clinic.•Base editing and prime editing are promising approaches for advanced T cell engineering but need further optimization of editing efficiency.
T cells engineered to express transgenes such as chimeric antigen receptors (CAR) or modified T cell receptors (TCR) represent a new pillar of cancer therapy. Use of CRISPR/Cas gene–editing tools now allows even stronger and more precise control over the fate and function of engineered T cell therapies, including multiplex genome editing to facilitate use of off-the-shelf allogeneic T cells and novel approaches which have the potential to overcome some of the limitations of canonical Cas9-mediated DNA cleavage. This review summarizes the CRISPR/Cas techniques that have been used in preclinical research and outlines those that currently being tested in clinical trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19
leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced ...into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.
•Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant.•Allogeneic stem cell transplantation after ...treatment with venetoclax in combination with HMA is associated with prolonged survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia ...(CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.
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