LMP April 3.docx

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Laboratory Medicine and Pathobiology
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LMP April 3 Cancer – a lot of commonality Most cancers develop as response to cytotoxic stress – so for example, gastrointestinal cancers, lung cancers or even homological cancers tend to develop at sites of inflammation – crhonic smoking leads to chronic inflammation in the lungs, killing many cells, and cells activate primordial ddefense mechanisms, behaving like bacteria and unicellular organisms to try and survive, activate pathways that lead to genetic instability – selection for cell population that can continually grow despite conditions in the microenvironment that tells them to not to – get this behaviour Hallmarks of cancer – Degenerates into disease with different cellular organisms but similar hallmarks – cancer cells develop insensitivity to that – encourage own blood supply – can grow indefinitely For a cell to grow indefinitely – glycolysis – fatty acid oxidation – all hallmarks of cancer Hallmarks are immunosuppressant and resistant to T cell – makes sense because immune system is designed to kill/limit situations that endanger the organism and so the immune system should be able to kill cancer cells – in order for cancer to develop – must develop mechanisms to resist T cells Why might T clel immunotherapy be effective treatment modality – the first justification is that cancer cells are not normal cells – in order to evolve, expresses new genes, mutated genes – gene expression patterns that differ from normal cells – recognize altered molecular patterns – cancer cells recognizable by cells of immune system – antigens that can stimulate T cells – in general, represent altered proteins or protein expression levels that from classic immunology – proteins degraded in the proteasome – peptides bound to MHC molecules – T cells through receptors activated, kill them – cancer antigens include products of mutated genes (p53 ex can get mutated – if disabled or mutated so no longer functional, tumour cells do not die when should not) – products of rearranged genes - chromosomal aberrations are major hallmark of cancer – genes can get juxtaposed, recombined, class rearrangement of leukemia – brc-chromosome 10 – result in fusion protein that is a kinase that never gets constitutively active – kinase can drive leukemia cells to grow but this is novel protein – adjoining region has never been seen before by immune system – as much an antigen as viral antigen that comes in during infection – BCR can get broken down and presented on MHC to serve as T cell targets – a lot of cancers lose differentiation state, acquire fetal characteristics, fetal genes would not necessarily be encountered by immune systems, so when expressed, become targets for T cells Gp100 and trp2 – involved in normal function of melanocytes – get overexpressed – higher levels than should be – they can now get recognized by T cels because amount of binding to MHC is such that immune system cannot recognize it Immune system arose to deal with viral infections – but principal same for cancer Viral antigens processed and presented by APC – come back to site of viral infection – bind to targets with appropriate antigens, get activated – T cells activated locally and kill the virally infected cells – tumour immunology – prinicpals are the same – T cells can recognize targets on tumour cells – can come into tumour microenvironment – eliminate antigen expressing tumour cells – like eliminate viral expressing cells T cell mediated immunotherapy can be effective strategy for cancer treatment – one of the few types of treatments for cancer that actually is curative is bone marrow transplantation – procedure offered to patients with certain types of leukemia – leukemia are cancers of the bone marrow – could be treated by high doses of cytotoxic chemotherapeutic drugs – if did not give intense therapy, did not kill of all the tumour cells – tumors relapsed – kill more leukemia cells, potentially get rid of all of them – kill off all normal hemoatostemic cells (die of plastic anema, not able to make red cells, neutrophils, platelets) Easy to grow hematopoetic stem cell system by putting bone marrow into patient, reconstitute patient – replace diseased bone marrow with bone marrow from normal patient – procedure pioneered in sixties and seventies – give patient high doses of chemotherapy – come in with bone marrow from atched donor, could eliminate leukemia but got graft-vers-host disease – this procedure transferred T cells from donor into patient along with hematopoetic stem cells – when doing transplant from matched donor, you collect bone marrow stem cells from bone marrow itself or from the blood – infuse into patient – T cells see MHC molecules of patient expressing proteins of patient normal gene products – T celsl from different environment, do not tolerate – activated by the antigens in the patient and get systemic activation of T cells that can cause significant damage to tissues, such as intestine, liver, skin – at the same time – T cells can recognize leukemia cells, which are also foreign – T cells clear leukemia cells but ALSO cause systemic GVH disease – so the idea was that in patients, mimic GVH and get the therapeutic effects of the GVH In bone marrow transplant, induce systemic generalized immunity – immunity comes form amount of genetic mismatch from donor T cells and patient in order for patient to survive procedure – the T cells used have to be such that they don’t recognize too many antigens in the patient, should not be too many genetic differences – and because most of the antigen disparity is transmitted through HLA system – one has to use a donor that is quite closely matched at the HLA loci – the best donor would be family member of sibling – Problem of GVH even if have matched onor – can be stressful to body – elderly less able to stand stresses of prolonged inflammation – BMT offered to younger patients with sibling donor and the problem is many patients with cancer are past this age, no longer eligible AC AD BC BD – four siblings – if AC has cancer, but the other three are not eligible to donate High age and low likelihood of elibible matched sibling – so low chance Minor antigens would serve as source of antigen to drive GVH disease so MUD transplants still toxic because can induce GVH disease Autotransplants – take patients own bone marrow, get rid of leukemia cells, use to reconstitute patients – but NO T CELL immunotherapy – tumour progressed because T cells recognized tumour cells so relapse a big problem Haploid identical transplants Vaccines – provide T cell therapy to patients – Receptor fused to tumour cell – get benefits of adoptive T cell therapy without GVH – simplest form of Graft versus tumour effect Make chimeric antigen receptor T cells – take T cells from patient, grow in lab and infect with construct that is a variant of antibody that has targeting moiety that can bind to target cell – when the T cell recognizes target, fires off, becomes activated and can kill target – chimeric antigen receptor T cells T cells circulate in patient – recognize CD18 variant B cells – include tumour cells – kill them without causing toxicity – no GVH disease – Works! Day 21 – bone marrow – brown are CD19 positive lymphoma cells – before procedure, lots of them, after procedure on day 41, less – then 177, normal BM develops This wipes out normal be cell compartment – Almost all T cells able to re ognize tuour reactive T cells – no cure for the most part 50% of patients relapsed despite having taken care of problem of tumour reactive T cells Cenral problem of immunotherapy is intrinsic resistance of tumour cells to T cells – central hallmark of cancer – now most important problem in T cell immunotherapy – Has a number of mechanisms by which it can shut off tumour reactive T cells – on an APC and tumour are all sorts of co-stimulatory molecules that send signals into the T cells to get activated – if have T cell binding to tumour cell, signal 1 is MHC peptide complex then there is signal two and signal three, costimulatory signals that are required to cooperate with the T cell receptor signal that allow T cell to proliferate, sustain activation, engage in functional immune response Molecules for signal 2 – CD28 on T cell that binds to CD8, CD6 – ox40 and CD70 are other costimulatory receptor stimate repairs that provide signals that sustain a productive T cell response – negative regulatory signals – molecule like PDL1 binds to PD1 on T cell and shuts down response or CTLA4 on T cell when it binds to CD8 or CD6 – on APC or tumour cell – also shuts things down – so tumour cells have high level expression of negative regulatory molecules – first ones dealt with are PDL1 and CTLA4 – logical approach would be to make antibodies against PDL1 or PD1 or against CTLA4 and infuse those into patient – block negative signal, productive T clel responses take place, clear tumour cells First trials of Abs against PD1 Microenvironment – tumour consists of T cell and tumour cells and more – tumour microenviroment seen as player in functional immune response Microevn has T cells, tumour cells, and supporting cels like B cells, macrophages, fibroblasts, and ideally what dendritic cells is support an effective T cell response against tumour cells – the type of immune response that one needs to get in microtumour env is TH1 response (where T cells make a lot of IFN gamma, and this cytokine activates cytotoxic cells, NK cells,
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