•NK cells play a critical role in cancer immune surveillance.•NK cellular therapy is safe but has some limitations.•Genetic engineering strategies are being employed to overcome these limitations.
...Recent advances in the field of cellular therapy have focused on autologous T cells engineered to express a chimeric antigen receptor (CAR) against tumor antigens. Remarkable responses have been observed in patients receiving autologous CD19-redirected T cells for the treatment of B-lymphoid malignancies. However, the generation of autologous products for each patient is logistically challenging and expensive. Extensive research efforts are ongoing to generate an off-the-shelf cellular product for the treatment of cancer patients. Natural killer (NK) cells are attractive contenders since they have potent anti-tumor activity, and their safety in the allogeneic setting expands the cell sources for NK cell therapy beyond an autologous one. In this review, we discuss advantages and limitations of NK cellular therapy, and novel genetic engineering strategies that may be applied to overcome some of the limitations. Next-generation engineered NK cells are showing great promise in the preclinical setting and it is likely that in the next few years CAR-engineered NK cells will be incorporated into the current armamentarium of cell-based cancer therapeutics.
Using cord blood as an allogeneic lymphocyte source, the investigators in this study infused natural killer cells that had been modified to express an anti-CD19 CAR into 11 patients with ...CD19-positive lymphoid cancers. Most patients had an antitumor response with very few toxic effects.
The advent of cellular immunotherapy in the clinic has entirely redrawn the treatment landscape for a growing number of human cancers. Genetically reprogrammed immune cells, including chimeric ...antigen receptor (CAR)-modified immune effector cells as well as T cell receptor (TCR) therapy, have demonstrated remarkable responses across different hard-to-treat patient populations. While these novel treatment options have had tremendous success in providing long-term remissions for a considerable fraction of treated patients, a number of challenges remain. Limited
persistence and functional exhaustion of infused immune cells as well as tumor immune escape and on-target off-tumor toxicities are just some examples of the challenges which restrain the potency of today's genetically engineered cell products. Multiple engineering strategies are being explored to tackle these challenges.The advent of multiplexed precision genome editing has in recent years provided a flexible and highly modular toolkit to specifically address some of these challenges by targeted genetic interventions. This class of next-generation cellular therapeutics aims to endow engineered immune cells with enhanced functionality and shield them from immunosuppressive cues arising from intrinsic immune checkpoints as well as the hostile tumor microenvironment (TME). Previous efforts to introduce additional genetic modifications into immune cells have in large parts focused on nuclease-based tools like the CRISPR/Cas9 system or TALEN. However, nuclease-inactive platforms including base and prime editors have recently emerged and promise a potentially safer route to rewriting genetic sequences and introducing large segments of transgenic DNA without inducing double-strand breaks (DSBs). In this review, we discuss how these two exciting and emerging fields-cellular immunotherapy and precision genome editing-have co-evolved to enable a dramatic expansion in the possibilities to engineer personalized anti-cancer treatments. We will lay out how various engineering strategies in addition to nuclease-dependent and nuclease-inactive precision genome editing toolkits are increasingly being applied to overcome today's limitations to build more potent cellular therapeutics. We will reflect on how novel information-rich unbiased discovery approaches are continuously deepening our understanding of fundamental mechanisms governing tumor biology. We will conclude with a perspective of how multiplexed-engineered and gene edited cell products may upend today's treatment paradigms as they evolve into the next generation of more potent cellular immunotherapies.
Cells often alter metabolic strategies under nutrient-deprived conditions to support their survival and growth. Characterizing metabolic reprogramming in the tumor microenvironment (TME) is of ...emerging importance in cancer research and patient care. However, recent technologies only measure a subset of metabolites and cannot provide in situ measurements. Computational methods such as flux balance analysis (FBA) have been developed to estimate metabolic flux from bulk RNA-seq data and can potentially be extended to single-cell RNA-seq (scRNA-seq) data. However, it is unclear how reliable current methods are, particularly in TME characterization. Here, we present a computational framework METAFlux (METAbolic Flux balance analysis) to infer metabolic fluxes from bulk or single-cell transcriptomic data. Large-scale experiments using cell-lines, the cancer genome atlas (TCGA), and scRNA-seq data obtained from diverse cancer and immunotherapeutic contexts, including CAR-NK cell therapy, have validated METAFlux's capability to characterize metabolic heterogeneity and metabolic interaction amongst cell types.
T cells engineered to express chimeric antigen receptors (CARs) have revolutionised the field of cellular therapy for cancer. Despite its success, this strategy has some recognised limitations and ...toxicities. Hence, there is growing interest in developing novel cellular therapies based on non‐αβ T‐cell immune effector cells, including NK cells that offer clear advantages in cancer immunotherapy. As a result, NK cells are being explored as an alternative platform for CAR engineering and are becoming recognised as important players in the next generation of cellular therapies targeting cancer. In this review, we highlight preclinical and clinical studies of CAR‐NK cells derived from different sources and discuss strategies under investigation to enhance the antitumor activity of these engineered innate immune cells.
NK cells can be derived from various sources (PB, UCB, HSC, iPSC, NK cell lines) and can be engineered to express a chimeric antigen receptor (CAR) to target various surface antigens on cancer cells. These CAR‐NK cells can be used as off‐the‐shelf adoptive cellular therapy to treat patients with various malignancies.
NK cell therapy for hematologic malignancies Mehta, Rohtesh S.; Randolph, Brion; Daher, May ...
International journal of hematology,
03/2018, Letnik:
107, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Natural killer (NK) cells are part of the innate immune system and represent the first line of defense against infections and tumors. In contrast to T cells, NK cells do not require prior antigen ...sensitization to induce cytotoxicity and do not cause graft-versus-host disease. These, along with other advantages, make NK cells an attractive candidate for adoptive cellular therapy. Herein, we describe the mechanisms of NK cell cytotoxicity, which is governed by an intricate balance between various activating and inhibitory receptors, including the killer cell immunoglobulin-like receptors (KIRs). We illustrate the advantages of NK alloreactivity as demonstrated in various types of hematopoietic stem cell transplants (HSCT), such as haploidentical, human leukocyte antigen-matched related or unrelated donor and umbilical cord blood transplant. We elaborate on different models used to predict NK cell alloreactivity in these studies, which are either based on the absence of the ligands for inhibitory KIRs, presence of activating NK cell receptors and KIR genes content in donors, or a combination of these. We will review clinical studies demonstrating anti-tumor efficacy of NK cells used either as a stand-alone immunotherapy or as an adjunct to HSCT and novel genetic engineering strategies to improve the anti-tumor activity of NK cells.
Integration of single-cell multiomics profiles generated by different single-cell technologies from the same biological sample is still challenging. Previous approaches based on shared features have ...only provided approximate solutions. Here, we present a novel mathematical solution named bi-order canonical correlation analysis (bi-CCA), which extends the widely used CCA approach to iteratively align the rows and the columns between data matrices. Bi-CCA is generally applicable to combinations of any two single-cell modalities. Validations using co-assayed ground truth data and application to a CAR-NK study and a fetal muscle atlas demonstrate its capability in generating accurate multimodal co-embeddings and discovering cellular identity.
Chimeric antigen receptor (CAR) engineering of T cells has revolutionized the field of cellular therapy for the treatment of cancer. Despite this success, autologous CAR-T cells have recognized ...limitations that have led to the investigation of other immune effector cells as candidates for CAR modification. Recently, natural killer (NK) cells have emerged as safe and effective platforms for CAR engineering. In this article, we review the advantages, challenges, and preclinical and clinical research advances in CAR NK cell engineering for cancer immunotherapy. We also briefly consider the feasibility and potential benefits of applying other immune effector cells as vehicles for CAR expression. SIGNIFICANCE: CAR engineering can redirect the specificity of immune effector cells, converting them to a much more potent weapon to combat cancer cells. Expanding this strategy to immune effectors beyond conventional T lymphocytes could overcome some of the limitations of CAR T cells, paving the way for safer and more effective off-the-shelf cellular therapy products.
Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study ...evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as “responders” or “nonresponders” to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.
•Blinatumomab is safe and feasible for use in B-ALL after allogeneic HCT.•The composition of a patient's T-cell subsets at the time of treatment is indicative of whether they will respond to blinatumomab.
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Cord blood (CB) offers a number of advantages over other sources of hematopoietic stem cells, including a lower rate of chronic graft-versus-host disease (cGVHD) in the presence of increased HLA ...disparity. Recent research in experimental models of autoimmunity and in patients with autoimmune or alloimmune disorders has identified a functional group of interleukin-10 (IL-10)-producing regulatory B cells (Bregs) that negatively regulate T-cell immune responses. At present, however, there is no consensus on the phenotypic signature of Bregs, and their prevalence and functional characteristics in CB remain unclear. Here, we demonstrate that CB contains an abundance of B cells with immunoregulatory function. Bregs were identified in both the naive and transitional B-cell compartments and suppressed T-cell proliferation and effector function through IL-10 production as well as cell-to-cell contact involving CTLA-4. We further show that the suppressive capacity of CB-derived Bregs can be potentiated through CD40L signaling, suggesting that inflammatory environments may induce their function. Finally, there was robust recovery of IL-10–producing Bregs in patients after CB transplantation, to higher frequencies and absolute numbers than seen in the peripheral blood of healthy donors or in patients before transplant. The reconstituting Bregs showed strong in vitro suppressive activity against allogeneic CD4+ T cells, but were deficient in patients with cGVHD. Together, these findings identify a rich source of Bregs and suggest a protective role for CB-derived Bregs against cGVHD development in CB recipients. This advance could propel the development of Breg-based strategies to prevent or ameliorate this posttransplant complication.
•Cord blood is a rich source of B cells with immunoregulatory function.•IL-10–producing B cells may protect against cGVHD after cord blood transplantation.
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