The researchers will take a personalized adoptive cell transfer and cancer vaccination immunotherapy approach to eradicating pancreatic cancer. Identification of expressed and immunologically active tumor-specific neoantigens in each patient will be performed in vitro and resulting neoantigens will be engineered into a gene incorporated into isolated peripheral blood mononuclear cells (PBMCs) and dendritic cells. Expression of endogenous antigens will be displayed via MHC class I, while a different cellular model will express an identical engineered gene with an additional signal sequence that will excrete the neoantigens subsequently displayed on the dendritic cells via MHC class II. CD4+ and CD8+ T cells will then be activated and incorporated into a vaccine delivered to the patient.
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Although both antigen types present as attractive targets for the development of cancer-eradicating immunotherapies, expression of TAAs in normal cells can trigger central and peripheral tolerance mechanisms that ultimately lead to selection of T cells with low-affinity receptors. Attempts to combat this effect through targeting of TAAs via high-affinity T cell receptors have been found to result in severe toxicities due to normal tissue destruction (Parkhurst et al. 2011). Unlike TAAs, tumor-specific neoantigens are not subject to central or peripheral tolerance and lack the ability to destroy normal tissues since their mutations arose from the tumor itself (Lu et al. 2016). Due to this key difference in the development of these antigens, the researchers will use tumor-specific neoantigens for the identification and subsequent targeting of pancreatic cancer cells through immunotherapy.
Immunology is largely based on the recognition and discrimination of self and non-self. Many pathogens have molecular signatures that allow the immune system to recognize and target them for destruction (Janeway Jr. et al. 2002). Unlike most pathogens, tumor cells lack these identifiable molecular signatures, allowing them to evade recognition as “non-self” and subsequently the immune response. Instead, cancer cells display tumor antigens that can be recognized by the immune system. Two such categories of these tumor antigens include tumor-associated antigens (TAAs) and tumor-specific neoantigens, which arise through different mechanisms. TAAs are expressed at low levels in normal tissues but are overexpressed in cancer cells, whereas tumor-specific neoantigens arise via non-synonymous mutations in the tumor itself (Lu et al. 2016). In some cases, these mutations lead to the expression of mutated peptides.
There are multiple TAAs common in pancreatic cancer that have been or are being targeted for immunotherapy. Ideally, treatment can incorporate vaccines for a few TAAs to account for patient tumor diversity. Carcinoembryonic antigen (CEA) is a particularly attractive TAA to incorporate into a vaccine as it is overexpressed in over 90% of pancreatic cancer. A clinical trial with 1 mg of the CEA vaccine CAP1-6D elicited robust CD8+ T cell responses in 7 out of 19 tested patients (Geynisman et al. 2013). Other potential targets for vaccines include KIF20-A (part of the kinesin family), KRAS, WT-1, and VEGF (Banerjee et al. 2018). I need to research each of these more to see which ones seem best to incorporate into our treatment plan. Activators of the STING protein, which induces pro-inflammatory responses through the INF-beta and NF-kappaB pathways, seems to contribute to the regression of tumors via T cell recruitment as well as enhance the responses of anti-CTLA4 and anti-PDL1 immunotherapies (Banerjee et al. 2018). More research is needed in this topic as well, but perhaps a cancer vaccine and a STING activator can be used in combination in hopes of creating an overall more effective immunotherapy.
For project 3 so far, I have been working on understanding the basics of the immune system as well as expanding my knowledge of possible immunotherapy routes to take in curing pancreatic cancer. Through many review articles, I have found that there are two approaches to anti-cancer immunotherapy: passive and active. Passive immunotherapy involves treatments with monoclonal antibodies, adoptive T cell transfers, and genetically engineered T cells, whereas active immunotherapy involves vaccine-mediated immunity via the administration of tumor-associated antigens (Banerjee et al. 2018). I would like to focus my research on the active side of immunotherapy. Due to genetic alterations or post-translational modification of proteins, cancer cells can express and display proteins that differ from their normal cell counterparts or are overexpressed in the tumor phenotype (Battaglia et al. 2016). These proteins are known as tumor-associated antigens (TAA) and fail to be recognized by the immune system. As a result, cancer cells that display TAAs are able to evade the normal destructive response of active CD8+ T cells. Cancer vaccines serve as methods of active immunotherapy that can stimulate the CD8+ T cell response to these TAAs and hopefully eradicate all cancerous cells that display them (Banerjee et al. 2018).
Cancer vaccine immunotherapies exploit the cross-presentation function of the immune system that allows antigen-presenting cells (APCs), especially dendritic cells (DCs), to phagocytose extracellular tumor-associated antigens (TAAs) and display them with MHC class I molecules to CD8+ T cells. Typically, extracellular antigens are phagocytosed by APCs and presented through MHC class II to CD4+ T cells, while endogenous antigens are presented through MHC class I to CD8+ T cells. This ability to display injected extracellular TAAs on MHC I is crucial in the activation of CD8+ T cells and subsequent eradication of the tumor. There are currently two known routes in the immune system for this mechanism of cross-presentation: cytosolic and vacuolar (Immune Response 2014). In the cytosolic route, the extracellular antigen is phagocytosed and then actively transported to the cytosol, where it is cleaved by a proteasome, transported to the ER, loaded onto MHC class I, and displayed on the plasma membrane. In the vacuolar route, the extracellular antigen is phagocytosed and at the ER is incorporated into an early endosome with lysosomal enzymes and MHC class I, which subsequently displays the antigen on the plasma membrane (Immune Response 2014). Further research is necessary to understand specific pathways involved in this cross-presentation mechanism.
This treatment exploits the cross-presentation function of the immune system that allows antigen-presenting cells (APCs), especially dendritic cells (DCs) to phagocytose extracellular antigens and display them with MHC class I molecules to CD8+ T cells. Typically, extracellular antigens are phagocytosed by APCs and presented through MHC class II to CD4+ T cells, while endogenous antigens are presented through MHC class I to CD8+ T cells. This ability to display extracellular (vaccine-injected) TAAs on MHC I is crucial in the activation of CD8+ T cells in killing the tumor. There are currently two routes for this mechanism of cross-presentation: cytosolic and vacuolar (Immune Response 2014). In the cytosolic route, the extracellular antigen is phagocytosed and then actively transported to the cytosol, where it is cleaved by a proteasome, transported to the ER, and loaded onto MHC class I. In the vacuolar route, the extracellular antigen is phagocytosed and then at the ER is incorporated into an early endosome with lysosomal enzymes and MHC class I, which subsequently displays the antigen on the plasma membrane (Immune Response 2014). The specific pathways involving cross-presentation remain unclear to me and requires further research. I also need to look into mechanisms of APC function, especially those of dendritic cells, so the cancer vaccine treatment will be able to work properly.
The poster is informative with three patient examples. Each example includes the age and gender of the patient as well as the tests run and the results found, both through images of the brain and corresponding graphs. Specific lines on the graphs that correspond to different regions of the brain are highlighted in the same color for easier visualization. There is no raw data and graphs are clean. Each example is located in the same region of the poster to allow for comparison across patients. However, there are no statistics on the results present. Overall, this poster is persuasive, clean, and succinct.
This poster includes the following sections: “Introduction,” “Methods,” “Results,” three sections of “Example Patients,” “Conclusions,” and “References & Acknowledgments.” These sections are presented in this order on three panels of the poster, reading left to right across the poster and vertically in each panel. This gives the poster a smooth flow and as a result, information regarding each section is easy to find. Within each section, the most important information is in bold and following information is presented in truncated language. Writing for the poster is in bullet point format and is direct. There are no grammatical, spelling, or typographical errors, however, conventions are slightly different as this poster is from the United Kingdom. Language is appropriate for scientific writing. In a clinical setting, this poster is structured to be as clear as possible. Images with colorful labeling aids in this process and conclusions are summarized in three short bullets.
This poster has an attractive design and includes cooler-toned colors such as blues, white, and black. It has a light blue background, however, each section is set in white boxes with navy blue headings. Text for headings is visualized in bold white, allowing the observer to clearly see the contents of each section. The layout of the poster has an intuitive flow and images are spaced throughout respective sections with appropriate and clear labeling. Images are more rainbow-colored or gray, allowing them to stand out from the background colors of the poster. A Helvetica-style font was used in poster construction with important descriptors in bold, such as headings (white) and main text (black). The font size for the body of the poster is sufficient, however, there is not a great distinction between heading and body font size. A larger text size would be useful in highlighting the contents of each section.