Throughout his career, the paradigm uniting Richard Edelson’s clinical and investigative programs is that they are so seamlessly blended that they are functionally one and the same. Each of his research projects has been inspired by clinical clues; each achieved scientific answer to those riddles has helped enhance clinical care. The first of his discoveries united a previously confusing set of artificially separated lymphomas, on the basis of his demonstration that all originated from the same specific subset of T lymphocytes. Because that cancer invariably presents in the skin, before disseminating throughout the body, he named it “Cutaneous T Cell Lymphoma” (CTCL), a designation that has stood the test of time. CTCL’s defining common cellular denominator is that it is a clonal expansion of malignantly transformed skin-homing CD4 “Cutaneous T Cells” which normally patrol the skin for infections and cancers. Just as melanoma arises from normal melanocytes, colorectal cancer from normal colon cells, etc., CTCL arises from from the large population of CD4 T cells biologically programmed to circulate between blood, skin and lymphatics with a normal responsibility for immune surveillance against dangerous cellular players and microbes.
Soon thereafter, he demonstrated that the CTCL’s distinguishing clinical features could be understood as amplifications of CTCL cell biologic features, many of which are retained from their normal cellular ancestors: (a) homing to the skin as a reflection of their derivation of “Cutaneous T Cells” which naturally cycle between skin and blood; (b) diagnostic accumulation of malignant cells in the T cell mantle in lymph nodes and avoidance of bone marrow; and (c) suppression of normal T cell immunity via production of suppressive cytokines. With colleagues, at the dawn of monoclonal antibodies, he used the clonally expanded CTCL cells to identify CD4 as the key marker for Th2 T cells and, by exclusion, CD8 as the key marker for cytotoxic T cells, the other most common T cell type. Each of these advances enabled a progressively clearer definition of CTCL, as a malignancy of CD4 skin homing T cells causing scientifically understandable clinical manifestations and offering therapeutically exploitable vulnerabilities to clinically target. Indeed, as understanding of T cell biology has continually matured, a high percentage of those accruing insights have become immediately applicable to comprehension of CTCL's behavior, facilitated its diagnosis and identified its therapeutically exploitable vulnerabilities.
At Columbia University’s College of Physicians and Surgeons, where he began his academic career, Edelson’s research team was the first to report that antibodies could be effective anti-cancer tools. He used anti-T cell antibodies to treat CTCL tumors and produce remissions. While encouraging and receiving much attention, these dramatic clinical responses were unfortunately transient, since microscopic remnants of the CTCL persisted and re-emerged, highlighting a need for more potent anti-CTCL biologic therapy. A pivotal serendipitous boost was provided when a therapy he devised to enhance the CTCL response to anti-T cell antibody administration surprisingly enlisted the normal immune system as partners, leading to a more powerful and persistent physiologic anti-tumor response in several patients with advanced otherwise therapeutically resistant CTCL. Because the extraordinary specificity, potency and safety of that new therapy could not, at first, be explained by known scientific principles, Edelson and colleagues recognized that the astonishing clinical responses offered a scientific GPS to the uncovering of a previously unknown major new therapeutic principle. It was quickly apparent to Edelson and his team, and quickly to investigators worldwide that, if the trigger for that mysterious natural physiologic anti-cancer response could be identified and harnessed, an ideal controllable multipurpose physiologic handle on immunotherapy might be at hand. But uncovering that underlying scientific principle and learning how to most effectively use it would turn out to be quite challenging.
The intervening decades became an Odyssey for Edelson and colleagues, overflowing with camaraderie with investigative co-travelers, thrilling patient responses and "aha moments", as progress towards resolution of the scientific mystery waxed and waned, but overall advanced. In excess of one thousand peer reviewed publications document that worldwide journey, with the largest single fraction contributed by the Edelson group. The goal of unlocking the outlines of the big mystery has now largely been accomplished, as elaborated in the 2019 Science Advances publication cited below. While that scientific pursuit proceeded, over thirty years, the novel therapy, originally named “Extracorporeal Photochemotherapy” or “ECP”, became the first FDA approved immunotherapy for any cancer and is now operative in the majority of university medical centers in the USA and Europe. A key clue to ECP's tight therapeutic collaboration with the physiologic immune system was that it not only yielded clinically important immunity against an advanced and stubborn cancer but also remarkably suppressed undesirable immune reactions against transplanted hearts and lungs, as well as graft-versus-host disease following stem cell transplants.
More than 70,000 patients with CTCL or transplant reactions have been treated with ECP, a usage driven by itss clinical efficacy and unusually favorable safety profile. The broad outlines of the now uncovered mechanism is traceable to ECP’s generation of physiologic dendritic antigen presenting cells (phDC), the previously elusive cellular master-switches of selective T cell immunity and tolerance. The current challenge to his research group, and a large cohort of colleagues throughout the world, is to learn to tailor this breakthrough insight into a broad range of personalized disease-specific immunotherapies. Because, in a controllable and tunable manner, platelets signal ECP-processed blood monocytes to become phDC to which the relevant antigens are transferred to phDC, the Edelson group has more aptly retitled the treatment “Transimmunization”.
The Edelson research team is now exploring the expanded application of Transimmunization to a spectrum of medical situations, ranging from immunization against emerging infectious agents and a broad range of solid malignancies (including ovarian and colorectal cancers and melanoma) to reactions against mismatched allografts and aggressive autoimmune disorders. Yale University has created a company, entitled "Transimmune, AG", funded and managed by accomplished international partners, to explore and develop the potential clinical applications of the patented underlying discoveries.
Edelson selected Immunology as his scientific area of interest, because it instrumentally influences the health of all body tissue. He chose Dermatology as his clinical specialty, because skin contains and displays all varieties of cellular elements in a highly organized, readily accessed and critically necessary manner. It was this tight interface between Immunology and Skin Disease that enabled his discoveries of CTCL, a physiologic treatment for the cancer and the manner in which monocytes can be naturally directed by platelet signaling to mature into physiologic dendritic antigen presenting cells (phDC), where and when they are required to initiate immunity against microbes or cancer or tolerance to self antigens.
Once phDC (physiologic dendritic antigen presenting cells) were established as the dominant mechanistic contributors to Transimmunization’s anti-tumor efficacy, a series of important conclusions could be drawn. Since, in the best responders, the treatment immunotherapeutically eliminated the malignant clone while apparently leaving normal T cell immunity intact, Transimmunization was clearly inducing a tumor-specific patient-specific clinically potent effect. Since, in a high percentage of recipients rejecting their transplanted hearts and lungs, despite conventional immunosuppression, Transimmunization also lessened the rejection without increasing opportunistic infections, the treatment was clearly capable of producing target tissue tolerance. Since limiting adverse reactions were exceedingly rare in these responders, the anti-cancer immunity and tissue tolerance had to be remarkably selective, a circumstance not reproduced by any “man-made” therapy. Transimmune's remarkable record of immunizing selectively against cancer, while also selectively suppressing destructive T cell attack of transplantation antigens, all largely in the absence of limiting adverse reactions, was entirely novel among immunotherapies and only matched in vivo by the Immune System itself. The attractive possibility that Transimmunization is actually a practical partnership with the normal immune system galvanized the ongoing search for the key guiding principle. Since DC are well known to be absolute requirements for physiologic selective immunity and tolerance, Edelson and colleagues recognized that the Transimmunization must somehow be producing and arming physiologic DC. With this insight, they then discovered that Transimmunization physiologically induces DC as detailed in the Science Advances paper listed below..
In the Transimmunization device, through which patient blood is extracorporeally processed over a two hour period, the following sequence has now been established. Soluble fibrinogen avidly adheres to the plastic surface, forming a substrate for equally avid platelet adherence and activation, just as occurs in wounds. The platelets are then signaled by the gamma chain of the adherent fibrinogen to instantaneously transpose p-selectin to the outside of the platelet surface. This p-selectin, by transiently binding to monocyte surface PSGL-1, then signals passaged blood monocytes to fortify the junction with platelets by capping the PSGL-1, leading to an immediate opening of calcium channels, culminating in NFkBd signaling of genes controlling monocyte-differentiation into phDC. This extracorporeally induced phDC are then tuned by photoactivated 8-methoxypsoralen (8-MOP) to become either immunogenic or tolerogenic to the antigens they are fed or already contain. This large scale production of phDC, cells normally difficult to access for tailoring to a clinical need for they are so rare in the blood stream, potentially opens doors to literally any disorder that can be impacted by the immune system. In the case of cancer, the patient-specific 8-MOP-damaged cancer cells can provide the ideal antigen substrate, while in the case of transplanted organ rejection or graft-vs-host disease following stem cell allografts, the antigenic source is provided by scavenger monocytes containing the tissue debris from target tissues.
Using a minaturized ECP apparatus we developed and which is scalable from mouse-to-man, we have demonstrated, as reported in two of the papers cited below, that we can effectively treat established experimental melanomas, as well colorectal and ovarian cancers, with this approach. Similarly, our colleagues at Northwestern University have shown that we can prolong organ allografts for up to a year in the absence of other immunosuppression. These preclinical studies encourage human trials, currently under consideration.
There are five active major projects in the Edelson laboratory: (1) dissection of the steps by which 8-MOP influences phDC into the tolerogenic mode; (2) testing of the premise that exosomes released from damaged tumor cells transfer relevant antigens to cross-presenting phDC; (3) enablement of intrafamilial haplotype-mismatched stem cell transplants through active tolerance; (4) development of a same-day simple method of subject-specific immunization against emerging infectious agents, such as SARS-CoV-2; and (5) augmentation of therapeutic graft-vs-tumor reactions.
Selected Publications (from More than 300) Relevant to the Above Narative
Edelson RL, Kirkpatrick CH, Shevach EM, Schein PS, Smith RW, Green I, Lutzner M. Preferential cutaneous infiltration by neoplastic thymus-derived lymphocytes. Morphologic and functional studies. Annals Of Internal Medicine 1974, 80:685-92.
Edelson R, Facktor M, Andrews A, Lutzner M, Schein P. Successful management of the Sézary syndrome. Mobilization and removal of extravascular neoplastic T cells by leukapheresis. The New England Journal Of Medicine 1974, 291:293-4.
Edelson RL, Brown JA, Grossman ME, Hardy MA. Anti-thymocyte globulin in treatment of T-cell lymphoma. Lancet 1977, 2:249-50.
Dermatology; Immunotherapy; Skin Diseases; T-Lymphocytes; Lymphoma, T-Cell, Cutaneous