So, uh, let me just take a sideways step and say that unfortunately, there's substantial complexity in our highly evolved immunobiology with multiple different kinds of cells. A rich repertoire of T cells and B cells as well as innate cells, and an equally dizzying number of cytokines, chemokines, and what are called cluster determinants on cell surface, making it uh devilishly difficult for somebody to um Dissect out what are the critical parts. I'd like to make an analogy to our understanding of rheumatoid arthritis. If you would ask me, uh, 30 or 40 years ago, uh which cytokine to target. In the dizzying array of cells and cytokines and rheumatoid arthritis, I would not have picked TNF, and yet now, some of the largest selling drugs in the world are means to inhibit the TNF molecule either directly with antibodies or through the soluble receptor. And so, uh, part of the argument I make is that Uh, with an allergy to rheumatoid arthritis, you don't really understand the disease until you have an effective therapeutic agent, which can change the biology and clearly we've taken people with crippling arthritis uh over. Uh Taken uh ulcerative colitis and uh Crohn's disease as the inflammatory bowel diseases by inhibiting TNF. And I'd like to argue, and I'll make an analogy that in cancer biology, there are many reasons to think that IL-2 is centrally important for the biology of cancer. Um, Uh, and that, uh, are applying it exogenously gave us some of the first clues that that was the case. So let me go back to the beginning, uh, when IO2 was first known as the T cell growth factor. It turned out to be 10 years later, we found out it was also a B cell growth factor and an NK cell growth factor. But a uh restricted cytokine, uh, in the sense that it is the only one of a rich array. Of T cell growth factors are defined by sharing a common gamma common chain of the IL 2 receptor, and that includes aisle 2, aisle 4, aisle 7, aisle 9, aisle 15, and aisle 21. It's the only one that has its own bona fide. To regulatory self. Uh, which serves as a glutton of IO2 capable of uh Taking up all of the IL2 in a microenvironment until you exceed either a certain degree of intimacy where IL2 is directly delivered from one cell in the tumor microenvironment to another, or alternatively, when it gets uh as we do with exogenous IL2, the highest levels that it gets above the um Threshold for uh exceeding what the regulatory cells are capable of consuming. The um Uh, early days of IL-2 were based on substantial mirroring studies that suggested that you could eradicate established tumors, uh, in, uh, mouse models, uh, that were in the skin, in the liver, in the lung, in the bone, in a variety of different locations, and it was with that confidence that we went in and started the IL-2 clinical trials. Uh at the NIH uh when I uh was there back in the early 80s. We've talked a little bit about the tumor microenvironment and uh it's complex panoply of cells. Which includes um Uh, the conventional alpha beta T cells, which are CD4 and CD8 T cells recognize an antigen in the context of peptides presented by class 2 MHC molecules for CD4 and by class 1 molecules for CDHs. In addition, there's a less well understood series. Of uh T cells that I studied along with Lou Mauss at the NCI. Uh, years ago, called gamma-delta T cells that are non-MHC restricted, but that are also very responsive to IL2 that appear to play a major role in recognizing. Uh, stress ligands and metabolites, uh, within epithelium and in fact are deposited early after embryonic. Uh, development, uh, in virtually every epithelial site, including the lung, gut, liver, kidney, breast, pancreas, etc. In addition, other IL-2 responsive cells include B cells. Uh, these can be found as isolated single cells in the tumor microenvironment, but are most often found organized in follicles, what are called germinal follicles inside uh lymph node-like structures that we call uh tertiary lymphoid sites, uh, that are found at sites of chronic inflammation such as cancer and rejecting allografts. Uh, many of these B cells are now being found to be not only responsive to IL-2, as not only a T cell growth factor, but also a B cell growth factor. That um Um, produces, uh, antibodies and uh to uh tumor antigens, both those on the cell surface as well as internal antigens, and serve as a unique uh antigen presenting cell in the tumor microenvironment. And then lastly, NK cells, uh, which express many of them, uh, as well, uh, the beta and gamma common chain of the IL2 receptor, but rapidly upregulate the IL2 receptor alpha chain, confirming, uh, conferring high affinity binding on those cells early after IL2 administration. Uh, during a normal immune response where IL2 is made locally and K cells thus are recruited in. As potential additional ancillary factors to the original T cells to magnify and extend the nature and quality of the immune response. When IL2 is given exogenously, uh, NK cells appear to be associated with much of the toxicity of high dose IL2 elaborating cytokines not only at the site of the tumor but at many other sites including the liver and other tissues that harbor or uh recruit NK cells. One other particular interesting aspect of the biology, which is important for people deeply understanding IL2 biology, is that the coordinating cell, the general in the uh Tumor microenvironment is a rare kind of dendritic cell called a BF3 CD103 positive dendritic cell. There are about 6% of the dendritic cells in the uh uh tumor microenvironment and like the dendritic. Cells in our own brains or uh peripheral nervous systems where you have each neuron generating up to 300 dendrites, these dendritic cells similarly can send out dendrites in the tissue, uh, several cell diameters away and coordinate the interaction of immune cells uh during the immune response to a cancer. Uh, interestingly, from the perspective of IO2. Um, they, when activated and mature, express. The IL2 receptor alpha chain and serve as a vehicle for capturing IL-2 and presenting it to the beta and gamma common chain of the uh Uh, expressing T cell factors. And so essentially, uh, dendritic cells serve to polarize and recruit and deliver IL2 to immune infectors in the tumor microenvironment. Uh, this is similarly done not just with IL-2, but also with IL-15, which was demonstrated by the late Tom Waldman, also from the National Cancer Institute. So if I might, um, Let me talk a little bit about how to visualize or how I currently visualize the uh A tumor microenvironment, that it's a series of innate. And uh adaptive immune cells that coordinately interact uh and have interacted uh over 7 to 10 years as the tumor has emerged. Uh, my own personal belief is that many of these immune cells were there from the very beginning, and as uh Bob Schreiber points out, go through a series of evolutionary steps in interaction with the evolving tumor. Where they first are capable of recognizing the tumor is being disordered, and that can be either through the gamma delta T cells or the alpha beta T cells, and eliminated. Actually eliminate. 99 or 99.9% of the tumor cells, or even 99.99% of the tumor cells. But as a consequence, the genomically unstable tumor cell. Um, is able to accrue additional mutations which allow the um immune system. To no longer completely eliminate the tumor, and this is a process known as equilibrium. And then eventually the tumor cells and these are largely the ones that we recognize first clinically, even when they first present, which have been under selective pressure by the immune system for 7 to 10 years, where they escape immune control. In that setting, what we're trying to do is not initiate new immune responses, but resurrect old immune responses that had been uh effective in controlling the tumor for many, many years, and that's part of the basis, not only for the efficacy of IL2. In kidney cancer and melanoma when given as an exogenous hormone, or for the many tumors for which checkpoint blockade has been effective targeting CLA4 on the T cell or PD1 on the T cell or PDL1 on the. Tumor cell, myeloid cell, or T cell itself.
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