Richard L Edelson, MD

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.

• Broder S, Edelson RL, Lutzner MA, Nelson DL, MacDermott RP, Durm ME, Goldman CK, Meade BD, Waldmann TA. The Sézary syndrome: a malignant proliferation of helper T cells. The Journal Of Clinical Investigation 1976, 58:1297-306.

• Edelson RL, Brown JA, Grossman ME, Hardy MA. Anti-thymocyte globulin in treatment of T-cell lymphoma. Lancet 1977, 2:249-50.

• Edelson R, Berger C, Gasparro F, Jegasothy B, Heald P, Wintroub B, Vonderheid E, Knobler R, Wolff K, Plewig G. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. The New England Journal Of Medicine 1987, 316:297-303.
• Kung PC, Berger CL, Goldstein G, LoGerfo P and Edelson RL. Cutaneous T cell lymphoma - characterization by monoclonal antibodies. Blood 1981. 57: 261-266. PMID: 6160893
• Berger CL, Hanlon D, Kanada D, Dhodapkar M, Lombillo V, Wang N, Christensen I, Howe G, Crouch J, El-Fishawy P, Edelson R. The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells. Blood 2002. 99:2929-2939. PMID: 15514008
• Choi J, Goh G, Walradt T, Hong BS, Bunick CG, Chen K, Bjornson RD, Maman Y, Wang T, Tordoff J, Carlson K, Overton JD, Liu KJ, Lewis JM, Devine L, Barbarotta L, Foss FM, Subtil A, Vonderheid EC, Edelson RL, Schatz DG, Boggon TJ, Girardi M, Lifton RP. Genomic landscape of cutaneous T cell lymphoma. Nature Genetics 2015. 47:1011-9.
• Berger CL, Hoffmann K, Vasquez JG, Mane S, Lewis J, Filler R, Lin A, Zhao H, Durazzo T, Baird A, Lin W, Foss F, Christensen I, Girardi M, Tigelaar R, Edelson RL. Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy. Blood 2010.
• Gonzalez AL, Berger CL, Remington J, Girardi M, Tigelaar RE, Edelson RL. Integrin driven monocyte to dendritic cell conversion in modified extracorporeal photochemotherapy. Clin Exp Immunol 2014. 175:449-57.
• Ventura A, Vassall A, Robinson E, Filler R, Hanlon D, Meeth K, Ezaldein H, Girardi M, Sobolev O, Bosenberg MW, Edelson RL. Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anti-Cancer Immunity. Cancer Res 2018. 78:4045-4058.
• Han P, Hanlon D, Arshad N, Lee J, Tatsuno K, Robinson E, Filler R, Sobolev O, Cote C, Rivera-Molina F, Toomre D, Fahmy T, Edelson, RL. Platelet P-selectin Initiates Cross-presentation and Dendritic Cell Differentiation in Blood Monocytes. Science Advances 2020. 6:1580-89.
• Alvero AB, Hanlon D, Pitruzzello M, Filler R, Robinson E, Sobolev O, Tedja R, Ventura A, Bosenberg M, Han P, Edelson RL, Mor G. Transimmunization resports immune surveillance and prevents recurrence in a syngeneic mouse model of ovarian cancer. Oncoimmunology. 2020. 9:1758869.
• Kazuki T, Yamazaki T, Hanlon D, Han P, Robinson E, Sobolev O, Yurter A, Rivera-Molina F, Arshad N, Edelson R, Galluzzi L. Extracorporeal photochemotherapy induces bona fide immunogenic cell death. Cell Death Dis. 2019. 10:578.