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CAR T Cells: Engineering Immune Cells to Treat Cancer - National Cancer Institute
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Pursuit of tumor-infiltrating lymphocyte immunotherapy speeds up
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Activated B cells become potent professional APCs only when appropriately activated. CD40L is a type II transmembrane protein, which exists as a trimer, inducing oligomerization of CD40 upon binding [ 4 ], a process that is critical for signaling via the CD40 receptor and likely accounts for the diverse biologic activities induced by different monoclonal antibodies [ 5 ]. CD40 acts a transmembrane signal transducer activating intracellular kinases and transcription factors within the cell.
These signaling cascades in B cells eventually promote germinal center formation, immunoglobulin isotype switch, somatic hypermutation, and formation of long-loved plasma cells or memory B cells [ 9 - 12 ]. This discovery resulted in the development of cell culture systems that allow the activation and expansion of B cells from peripheral blood [ 14 ]. In the late s, Schultze et al. Ex vivo-generated CD40B cells possess potent immunostimulatory properties and are capable of priming CD4 and CD8 T cells in vitro and in vivo [ 16 - 18 ].
Over the subsequent years, the antigen-presenting function of B cells was characterized in more detail and the concept of B cell-based cancer vaccines was increasingly refined. Several experimental studies in different tumor models confirmed that vaccination with CD40B cells could induce effective antitumor CD4 and CD8 T-cell responses. In , Biagi et al. They transduced autologous leukemic B cells isolated from patients with chronic lymphocytic leukemia CLL with an adenoviral vector that contained the human CD40L gene and reinfused these cells together with transduced autologous CLL cells that expressed interleukin IL Unfortunately, the induced T-cell responses were only transient and unable to overcome tumor-induced immunosuppression in the long term.
In spite of these disappointing results, this study provided a first proof-of-concept for B cell-based cancer immunotherapy and demonstrated that antitumor T-cell responses can be induced by activated antigen-presenting B lymphocytes.
B cells can be activated by a variety of stimuli to acquire immunostimulatory capacity, including B-cell receptor BCR binding to antigen and toll-like receptor-mediated signals. However, signals transmitted via CD40 have consistently been found to be the most potent inducer of many features of potent APCs [ 2 ]. Several strategies have been investigated to exploit CDCD40L interaction for the generation of antigen-presenting B cells summarized in Table 1 for human B cells [reviewed in 21 ].
These include the usage of recombinant soluble CD40L proteins [ 22 - 25 ], triggering CD40 with agonistic monoclonal CD40 antibodies [ 26 , 27 ], and CD40L-expressing feeder cells [ 28 - 30 ]. A number of factors affect the extent of B-cell activation by CDmediated signals. For instance, the effect of anti-CD40 antibodies on B-cell activation is determined by the exact location of their binding to CD40 [ 5 ]. Another factor that crucially determines the extent of B cell activation is the degree of CD40 crosslinking.
It has long been established that optimal bioactivity is only observed when using a multimerized form of the CD40L homotrimer, thus allowing clustering on the cell surface [ 31 - 33 ]. Clustering of the CD40L is not elicited by monoclonal anti-CD40 antibodies, thus only inducing activation, but not proliferation of B cells [ 31 - 33 ]. CD40L- expressing feeder cells naturally provide a multimerized form of the CD40L, but to avoid xenogeneic components in clinical products recombinant soluble CD40L is the preferred choice for a clinical application of B cells.
Typically, human peripheral blood mononuclear cells PBMCs or purified B cells are cultured for a period of at least 14 days in the presence of the soluble CD40L and IL-4 [ 22 , 23 ], in which the addition of IL-4 is necessary for B-cell proliferation [ 34 ]. These culture conditions result in a profound polyclonal activation of B cells that leads to an approximately fold expansion [ 15 , 35 , 36 ] and the acquisition of an antigen-presenting phenotype [ 15 , 37 , 38 ].
Combination of CD40L stimulation with CpG as proposed by some studies [ 18 , 40 ] has no further impact on the expression of activation markers or proliferation of B cells, while additional stimulation with LPS further increases the activation of B cells [ 18 , 40 ]. Increased expression of MHC and costimulatory molecules on CD40B cells correlates with the acquisition of antigen-presenting functions. CD40 activation results in improved antigen processing and presentation [ 41 ], typically via the classical MHC class II pathway [ 18 , 42 ], but also a distinct nonclassical, cytosolic MHC class II pathway [ 43 ].
Becker et al. However, epoxomicin sensitivity was not observed in DCs, suggesting an antigen-processing mechanism unique to CD40B cells. Lapointe et al. CD40B cells fulfill crucial requirements for their use as APCs in cancer immunotherapy: 1 they can be consistently generated from peripheral blood, 2 they are relatively insensitive towards tumor-derived immunosuppressive mechanisms, 3 they do not induce tolerance by themselves, and 4 they are well tolerated upon infusion in terms of toxic side effects.
It has been shown that this is even feasible in cancer patients [ 35 , 51 ]. Furthermore, the culture system for generating CD40B cells is relatively easy and inexpensive. Therefore, one might suppose that they have similar effects on antigen-presenting B cells. However, activated B cells turned out to be relatively resistant to inhibition by tumor-associated immunosuppressive molecules.
Concerning the induction of tolerance by administration of activated B cells, the mode of activation is of considerable importance. Toxic side effects of CD40B-cell administration were not observed in in vivo in studies with mice or dogs. Body weight and survival remained unchained under all tested conditions. No abnormal lymphocytic infiltration, structural tissue injury, or indications of inflammation could be detected in histological analyses of heart, lung, liver, spleen, and kidney [ 68 ].
Only few studies investigated antigen presentation by CD40B cells or the influence of their administration on tumor growth in vivo summarized in Table 2. Sorenmo et al. However, they detected a significant improvement in the rate of durable second remission and survival between vaccinated and nonvaccinated groups. Since dogs are a widely accepted animal model to evaluate safety and efficacy before proceeding to a clinical trial, this study was an important step towards a clinical application of CD40B cells. More promising results in terms of cancer treatment were reported in mice.
F10 melanomas or E. G7 lymphomas, respectively [ 71 , 72 ]. After activation with anti-CD40 antibodies, they were adoptively transferred into syngeneic tumor-bearing mice. In combination with activated T cells, CD40B-cell administration resulted in the reduction of spontaneous metastases. Moreover, combining adoptive transfer of B cells with chemotherapy or total body irradiation significantly inhibited tumor growth. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume 1. Article Contents. Mechanisms of cancer immune evasion.
- Uneven Development in the Third World: A Study of China and India.
- Lymphocytes in Immunotherapy of Cancer.
- Immunotherapy Treatment To Fight Cancer | Cleveland Clinic.
- Lymphocytes in Immunotherapy of Cancer | Paul Koldovsky | Springer.
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Cancer immunotherapy strategies. Immunotherapy drug resistance and combination therapy. Prediction of responsiveness of cancer patients to immunotherapy. Conclusion and future directions. Conflict of interest statement. Recent updates on cancer immunotherapy Ming Liu. Oxford Academic.
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Abstract Traditional cancer therapies include surgery, radiation, and chemotherapy, all of which are typically non-specific approaches. Figure 1. Open in new tab Download slide. Table 1. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Search ADS. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the VE BRAF oncogene. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.
Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Gefitinib plus interleukin-2 in advanced non-small cell lung cancer patients previously treated with chemotherapy. Evaluating the cellular targets of antiBB agonist antibody during immunotherapy of a pre-established tumor in mice.
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Functional optimization of agonistic antibodies to OX40 receptor with novel Fc mutations to promote antibody multimerization. Indoleamine 2,3-dioxygenase IDO : Only an enzyme or a checkpoint controller? IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity.
Ferrari de Andrade. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sipuleucel-T provenge injection: the first immunotherapy agent vaccine for hormone-refractory prostate cancer. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. For commercial re-use, please contact journals. Issue Section:. Download all figures.