question: Why can't we engineer or or artificially increase the amount of T-Cells a person has to combat cancer?
comment: We can. And we did. It's called CAR-T cell therapy.
passages: In order to have efficient eradication of cancer cells, the immune system cells should be able to both populate in the secondary lymphoid organs for a long-lasting effect and target a shared variety of tumor cells as opposed to one, specific cancer cell. In the ALECSAT method, several different cells are activated to accomplish this. Cytotoxic T lymphocytes (CTL) are activated to target the cells that present proteins characteristic of tumor cells Some tumor cells, however, do not present an antigen due to lack of a major histocompatibility complex (MHC) and therefore cannot be recognized by the CTLs. The cells that do not present an antigen are targeted by activated NK cells, leaving little opportunity for any cancer cells to escape. CTLs and NK cells are both effector cells so helper T-cells (T) are also prepared in order to create memory cells for long term resistance toward tumor cells. T helper 1 (TH1) cells, when injected with overexpressed tumor antigens, have been shown to enhance migration of antigen-presenting cells (APCs) into the draining lymph node in mice, further enhancing immune response through activation of CTLs.
   Multiple ways of producing and obtaining tumour targeted T-cells have been developed. T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. Subsequent activation and culturing is performed "ex vivo," with the results reinfused. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens.
  
  As of 2014, multiple ACT clinical trials were underway. Importantly, one study from 2018 showed that clinical responses can be obtained in patients with metastatic melanoma resistant to multiple previous immunotherapies.
   A number of pre-clinical and clinical studies have demonstrated that vaccines against pathogens, bystander (non-pathogenic) proteins, tumor-associated antigens, or whole tumor cells, can induce specific T-cell mediated immune responses. A number of approaches have been considered to amplify T cell mediated immune responses(e.g. IL-2, CTLA-4, IL-7, CD137), and some of these have shown clinical efficacy in eliminating particular types of cancer, most notably melanoma and renal cell carcinoma.
  
  Section::::Basic Immunology.:T-Cell Homeostasis and Homeostatic Proliferation.
   Antigens encoded by cancer-germline genes such as "MAGEA1" and "MAGEA3" have been used in the form of antigenic peptide, protein or recombinant viruses harbouring a sequence coding for the antigen. Clinical responses have been observed in a small minority ( 10%) of patients. However, so far, large randomized trials have failed to demonstrate significant benefit to the patients.
  
  Melanocytic differentiation antigen gp100 has also been used as a vaccine and extended survival has been observed in the group of vaccinated patients.
   Due to the extremely polymorphic nature of MHC class II molecules, simple transfection of these proteins does not provide a practical method for use as a cancer vaccine. (Chamuleau et al., 2006) Alternately, two other methods have been examined to upregulate the expression of these proteins on MHC class II cells. The first is treatment with IFNγ, which can lead to increased MHC class II expression. (Trincheiri and Perussia, 1985, Fransen L, 1986) A second, more effective approach involves targeting the genes responsible for the synthesis of these proteins, the CIITA or class II transcription activator. Selective gene targeting of CIITA has been used ex vivo to allow MHC class II cells to become MHC class II (Xu, et al. 2000). upregulation of CIITA also causes an increased expression of Ii, and as such, must be used in conjunction with the antisense techniques referred to earlier (Qui, 1999). In some forms of cancer, such as acute myeloid leukemia (AML) the cells may already be MHC class II, but because of mutation, express low levels on their surface. It is believed that low levels are seen as a direct result of methylation of the CIITA promoter genes (Morimoto et al., 2004, Chamuleau et al., 2006) and that demethylation of these promoters may restore MHC class II expression (Chamuleau et al., 2006).
   Studies have indicated that CD4+ T cells in "vivo" have the capacity to enhance CD8+ T cell activity and, most importantly, help to maintain the immune response for sustained periods of time. Therefore, it seems likely that optimal antitumor activity can only be achieved if both CD4+ and CD8+ tumor-specific T cells are induced. The inclusion of CD4+ epitopes into MAGE-3 vaccination studies has recently been facilitated by the identification of several HLA-DR-restricted and one HLA-DP4-restricted epitope.
  
  Section::::Clinical trials.
   CD4+ T cells promote antitumor immunity by numerous mechanisms including enhancing antigen presentation, co-stimulation, T cell homing, T cell activation, and effector function. These effects are mediated at sites of T cell priming and at the tumor microenvironment. Several cancer vaccine approaches induce durable CD4+ T cell responses and have promising clinical activity. 
  
  This kind of vaccine can be realized by DNA recombinant fusion protein expressed in E. coli. The protein named MAGE-3 has already been used in lung cancer treatment and received very good feedback.
  
  Section::::Advantages.
   The use of TILs as an adoptive cell transfer therapy to treat cancer was pioneered by Dr. Steven Rosenberg and colleagues at the Surgery Branch of the National Cancer Institute (NCI). Rosenberg and colleagues have conducted clinical trials for more than two decades using TIL adoptive cell therapy for melanoma. TIL adoptive cell therapy is now a routine regimen in centers across the world, including MD Anderson Cancer Center, where the objective response rates originally observed at the NCI have been reproduced. Several centers currently have established TIL therapy protocols for the treatment of melanoma, including the MD Anderson Cancer Center in Houston, Texas, Ella Institute in Sheba Hospital, Israel, and Copenhagen University Hospital in Herlev, Denmark.
   CD4+ T cells has already been successfully induced in nonsmall cell lung cancer patients vaccinated with MAGE-3 recombinant protein. Two cohorts were analyzed: one receiving MAGE-3 protein alone, and one receiving MAGE-3 protein with adjuvant AS028. Of nine patients in the first cohort, three developed marginal Ab titers and another one had a CD8+ T cell response to HLA-A2-restricted peptide MAGE-3 271-279. In contrast, of eight patients from the second cohort vaccinated with MAGE-3 protein and adjuvant, seven developed high-titered Abs to MAGE-3, and four had a strong concomitant CD4+ T cell response to HLA-DP4-restricted peptide 243-258. One patient simultaneously developed CD8+ T cells to HLA-A1-restricted peptide 168-176. The novel monitoring methodology used in this MAGE-3 study established that protein vaccination induces clear CD4+ T cell responses for further evaluating integrated immune responses in vaccine settings and for optimizing these responses for clinical benefit.
   The main goal of the therapeutic vaccines is to elicit cellular immunity. They should prime naive T cells as well as induce transition from chronically activated non-protective CD8 T cells to healthy CD8 T cells able to produce cytotoxic T lymphocytes (CTLs), that recognise and eliminate cancer cells in an antigen-specific way and also provide long-lived memory CD8 T cells that will act to prevent relapse. The most critical step in vaccination is the effective presentation of cancer antigens to T cells and because of DCs are the most efficient antigen presenting cells, they are the promising option for improvement of therapeutic vaccines.
   Gene switches were designed to enhance safety of the treatment. Kill switches were developed to terminate the therapy should the patient show severe side effects. Mechanisms can more finely control the system and stop and reactivate it. Since the number of T-cells are important for therapy persistence and severity, growth of T-cells is also controlled to dial the effectiveness and safety of therapeutics.
  
  Although several mechanisms can improve safety and control, limitations include the difficulty of inducing large DNA circuits into the cells and risks associated with introducing foreign components, especially proteins, into cells.
  
  Section::::Bioethics and security.
   Important tumor regressions were observed in patients treated with IL-2 and very large numbers (≥10) of expanded TILs (tumor-infiltrating lymphocytes). Patients injected with expanded TILs directed against gp100 showed tumor regression but also significant adverse side effects such as uveitis. Adoptive transfer of TILs can increase the survival of melanoma patients when it is used as an adjuvant therapy, "i.e." after a surgery and before the appearance of metastases.
   Solid tumors have presented a more difficult target. Identification of good antigens has been challenging: such antigens must be highly expressed on the majority of cancer cells, but largely absent on normal tissues. CAR-T cells are also not trafficked efficiently into the center of solid tumor masses, and the hostile tumor microenvironment suppresses T cell activity.
  
  Section::::Cancer treatment.:Clinical studies and FDA approvals.
   At least two adjuncts are added to the dendritic cells. One adjunct excites a general aspect of the body's immune response; another excites a more tumor-specific response. This mixture is then injected into the patient's tumor. There, the dendritic cells are expected to scavenge tumor proteins, then find their way to the local lymph node for presentation of the tumor protein antigens to T cells and B cells. The activated T and B cells then travel to the tumor and kill tumor cells. Ruptured tumor cells release more mutant proteins that are picked up by dendritic cells and other immune cells, and are carried to the lymph nodes to excite still more B and T cells. Theoretically, this cycle repeats, accelerates, then levels off at a high but safe level. The Phase 1 trial that finished enrollment in July, 2014 seeks to confirm this.
   Because of the logistic difficulty of obtaining tumor-specific T cells via the ex vivo expansion of tumor-infiltrating cells, a number of studies have examined inducing these cells in vivo by vaccination. Levitsky et al., at Johns Hopkins, in a series of pre-clinical studies demonstrated that vaccine-induced T cells could be considerably more effective when re-infused into lymphodepleted recipients. Subsequently, a clinical study in patients with multiple myeloma conducted by June et al., demonstrated that a standard vaccination against pneumonia could induce a T-cell-mediated response to the vaccine and that re-infusing these T cells after an extremely lymphodepletive therapy –autologous stem cell transplant – could significantly enhance that response.
   Tumor-specific antigens encoded by mutated genes were considered to be unsuitable for vaccines because they are different for every patient. However, these are very promising antigens and the progress in genome sequencing appears now to make it possible to identify such antigens for individual patients and use them as personalized vaccines.
   aAPCs remove the need to harvest patient specific APCs such as dendritic cells (DCs) and the process of activating the DCs in the stimulation of antigen-specific T cells. As specific cancer antigens have been discovered, these antigens can be loaded to aAPCs to successfully stimulate and expand tumor-specific cytotoxic T cells. These T cells can be then re-infused or adoptively transferred into the patient for effective cancer therapy. This technology is currently being tested within laboratories for potential use in cancer therapy and to study the mechanisms of endogenous APC signaling.
   The main risk of prolonged immune stimulation for cancer prevention is the development of autoimmune diseases. Most antitumor immune responses are autoimmune, because most tumor antigens are also expressed by normal cells, but it must be considered that autoimmune responses do not necessarily evolve into autoimmune diseases. The limited autoimmunity triggered by cancer immunoprevention did not cause overt autoimmune diseases in preclinical mouse studies, however this is an issue that will require careful monitoring in early clinical trials.
   Section::::Use in adoptive T cell transfer therapy.:Process.
   microvesicles from various tumor types can express specific cell-surface molecules (e.g. FasL or CD95) that induce T-cell apoptosis and reduce the effectiveness of other immune cells. microvesicles released from lymphoblastoma cells express the immune-suppressing protein latent membrane protein-1 (LMP-1), which inhibits T-cell proliferation and prevents the removal of circulating tumor cells (CTCs). As a consequence, tumor cells can turn off T-cell responses or eliminate the antitumor immune cells altogether by releasing microvesicles.
  
  Section::::Relevance in disease.:Cancer.:Impact on tumor metastasis.
   Infusions of T cells engineered to express a chimeric antigen receptor that recognizes an antigen molecule on leukemia cells could induce remissions in patients with advanced leukemia. Logistical challenges are present for expanding T cells and investigators are working on applying the same technology to peripheral blood NK cells and NK-92.
   Many head and neck cancers are able to escape immune responses in a variety of ways. Once such example is through the production of pro-inflammatory and immunosuppressive cytokines. This can be achieved when the tumor recruits immunosuppressive cell subsets into the tumor's environment. Such cells include pro-tumor M2 macrophages, myeloid-derived suppressor cells (MDSCs), Th-2 polarized CD4 T-lymphocytes, and regulatory T-lymphocytes. These cells can then limit the responses of T cells through the production of cytokines and by releasing immune-modulating enzymes.
  
  Section::::Escape from vaccination.
  
  Section::::Escape from vaccination.:Consequences of recent vaccines.
   T cells must reproduce after arriving at the tumor site to further increase their numbers, survive the TME's hostile elements and migrate through the stroma to the cancer cells. The TME obstructs all three activities. The draining lymph nodes are the likely location for T cell clonal reproduction, although this also occurs within the tumor. Preclinical models suggest that the TME is the major site of cancer-specific T cell cloning and that the CD8 T cell replicative response there is orchestrated by the CD103, Baft3-dependent DC, which can efficiently cross-present cancer cell antigens, suggesting that therapeutic interventions that enhance CD103 contribute to tumor control. Among such strategies are antibodies to the interleukin-10 receptor (IL10R). In a mammary carcinoma mouse model it neutralized the effects of TAM-produced IL10, relieved the suppression of IL12 production by intratumoral DCs and improved the CD8 T cell–dependent antitumor effects of chemotherapy. A similar outcome was achieved by neutralizing macrophage colony-stimulating factor 1, which impaired the intratumoral accumulation of TAMs. Another strategy is the administration of antibody-interferon-β (IFN-β) complexes that activate intratumoral DCs to cross-present antigen to CD8 T cells. They are targeted against oncogenic receptors such as epidermal growth factor receptor (EGFR).
   A specialised type of white blood cell, known as cytotoxic T lymphocytes (CTLs), are produced by the immune system and are able to recognise specific markers on the surface of various infectious or tumour cells, causing them to launch an attack to kill the harmful cells. Thence, immunotherapy with functional antigen-specific T cells has potential as a therapeutic strategy for combating many cancers and viral infections. However, cell sources are limited, because they are produced in small numbers naturally and have a short lifespan.
   Clinical vaccination studies using full-length recombinant proteins have the advantage that this form of Ag potentially includes the full range of epitopes for CD4+ and CD8+ T cells. In addition, it is likely that protein vaccination leads to presentation of epitopes in the context of various HLA alleles, and therefore this type of vaccine should be applicable to any patient regardless of HLA restriction. To date, only one clinical study using MAGE-3 protein as a vaccine has been reported. Using a cloning approach, one patient was shown to have a CD4+ T cell response to HLA-DR1-restricted peptide 267-282.
  
  Section::::Future work.
  
presuppositions: Humans can't engineer or artificially increase the amount of T-Cells to combat cancer. We can't increase the amount of T-Cells a person has.
corrections: Humans can engineer or artificially increase the amount of T-Cells to combat cancer which is called CAR-T cell therapy. We can and it's called CAR-T cell therapy.
raw_presuppositions: Humans can't engineer or artificially increase the amount of T-Cells to combat cancer. We can't increase the amount of T-Cells a person has.
raw_corrections: Humans can engineer or artificially increase the amount of T-Cells to combat cancer which is called CAR-T cell therapy. We can and it's called CAR-T cell therapy.