Immune -Check Points - Inhibitors and allo-immunity Mohammadreza - PowerPoint PPT Presentation

Immune -Check – Points - Inhibitors and allo-immunity Mohammadreza Ardalan Professor of Nephrology Kidney Research Center Tabriz University of Medical Sciences

Unraveling the Complexity of T Cell Activation • By the late 1980s, it was known that simple engagement of peptide/MHC complexes by the antigen receptor is insufficient for activation of T cells and may render them anergic. J. Immunol. 142, 2617 – 2628. • In order to become fully activated, T cells must encounter antigen in the context of (APCs), which provide costimulatory (B7-1 and B7-2) that will engage their ligand, CD28, on T cell . Annu. Rev. Immunol. 23, 515 – 548.

Unraveling the Complexity of T Cell Activation • By the mid-90s, it became clear that T cell priming elicits not only induction of more T cell responses but also a parallel program that will eventually stops the response. The critical inhibitory program is mediated by CTLA-4, a homolog of CD28 that also binds B7-1 and B7-2, although with much greater avidity . CD28.Walunas, T.L., (1994),Immunity 1, 405 – 413.

Unraveling the Complexity of T Cell Activation • Thus, activation of T cells as a result of antigen receptor signaling and CD28 co- stimulation is followed not only by positive induction , but also by development of an inhibitory program mediated by CTLA-4, ultimately T cells proliferation stops. • If eradication of an antigen has not been completed by the time, inhibitory signal is triggered, T cells will be turned off and will be unable to complete the task. • vaccines used to stimulate antigen receptor signaling may actually serve to strengthen the ‘‘ off ’’ signal as a result of additional induction of ctla-4 expression. Cell 161, April 9, 2015

Immune Checkpoint Therapy: The Clinical Success • In 90s, it was found that, blocking antibodies to CD28 impaired anti- tumor responses in mice, while blocking antibodies to CTLA-4 enhanced anti-tumor responses . Science 271, 1734 – 1736 . • The success of CTLA-4 blockade raised two compelling points. First, because the target molecule was on the T cell and not the tumor cell the strategy would work on many different histologic tumors, Second, its blockade could allow the efficacy of tumor vaccines development. J. Exp. Med. 206, 1717 – 1725

Immune Checkpoint Therapy: The Clinical Success • CTLA-4 blockade was translated to the clinic with a fully human antibody to human CTLA-4 (ipilimumab,). Tumor regression was observed in patients with a variety of tumor types, including melanoma, renal cell carcinoma, prostate cancer, urothelial carcinoma, and ovarian cancer. J. Immunother. 30, 825 – 830.

Immune Checkpoint Therapy: The Clinical Success • Another T-cell-intrinsic inhibitory pathway is mediate by PD-(programmed death 1) and its ligand PD-L1. ( PD-1 was initially cloned in 1992 ,involved in negative selection of T cells in the thymus), preclinical studies in animal evaluated anti-PD-1 andanti-PD-L1 antibodies as immune checkpoint therapies to treat tumor. Annu. Rev. Immunol. 26, 677 – 704. • PD-1 is expressed in activated T cells. unlike CTLA-4, PD-1 inhibits T cell responses by interfering T cell receptor signaling as opposed to outcompeting CD28 for binding to B7.

Immune Checkpoint Therapy: The Clinical Success • PD-1 also has two ligands, PD-L1 and PD-L2. PD-L2 is predominantly expressed on APCs, whereas PD-L1 can be expressed on many cell types, including immune cells, epithelial cells,and endothelial cells. Antibodies targeting PD-L1 have shown clinical responses in multiple tumor types, Nature 515 562-558, 2014 A phase III clinical trial that treated patients with metastatic melanoma by anti-PD-1 antibody (nivolumab) demonstrated improved responses N. Engl. J.Med. 372, 320 – 330 . •

• Another co-stimulatory molecule is inducible co-stimulator (ICOS), a member of the CD28/B7 family whose expression increases on T cells upon T cell activation. ICOS+ effector T cell increases after patients receive treatment with anti-CTLA-4. Proc. Natl. Acad. Sci. USA 105, 14987 – 14992.2008

Active ADs and ICIs • low-grade AD flares seem to occur. It appears that the effectiveness of ICIs is not lowered in this special population. Overall, ICIs could be considered reasonable to use in patients with advanced cancer and preexisting minimally active or asymptomatic Ads.

ICIs ,autoimmunity ,allo-immunity • In • Because of the risk of exacerbation of underlying autoimmune or inflammatory disease, patients with preexisting autoimmune disorders (ADs) , those receiving systemic immunosuppression for organ transplantation have been universally excluded from immune-checkpoint inhibitors clinical trials. • Thus, the safety and effectiveness of ICI therapy in this special population are unknown. • Cancer. 2017;123:1904e1911

ICIs in SOD • Solid organ transplantation (SOT) recipients have been excluded from clinical trials because of worries concerning alloimmunity, org rejection, and an increased risk of developing de novo cancer after SOT

ICIs in SOD • case reports and retrospective studies have found a higher trend of transplant rejection among patients receiving anti-PD-1 versus anti-CTLA-4 agents. • Graft rejection appears to be an early PD-1 inhibitor adverse event the median time to rejection is 8 days. • Lipson EJ N Engl J Med. 2016

ICIs in SOD • It remains unclear which immunosuppression regimen is most efficacious at reducing the risk of graft rejection without completely compromising ICI efficiency.

ICIs in SOD • Concomitant treatment with ICI and calcineurin inhibitor (CNI), which was associated with a lower antitumor response; in a nine patients who were left on full dose of CNI during ICI therapy, rejection was not observed but tumor response was seen in only one of nine patient. • J Immunother. 2017;40:277-281 . • Interestingly, several transplant patients experienced a tumor response without rejection when their regimen contained sirolimus. • N Engl J Med. 2017;376:191

ICIs in SOD • Interestingly, numbers of CD4 T cells and serum IFN-g levels increased, with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Nat Commun. 2019;10:4712 . • From this point of view, sirolimus may be a good alternative in SOT recipients receiving ICIs

ICIs in SOD • No specific guidelines on the management of acute cellular rejection in ICI- treated patients are available. • In general, i.v. solumedrol 250-500 mg daily for 3 days being the most common first-line strategy, but 80% have experienced graft loss despite aggressive treatment with high-dose CS. • J Immunother Cancer. 2019;7:106 .

ICIs in SOD • considering that metastatic melanoma is a life-limiting condition, the possible survival benefit associated with ICI treatment may be worth the risk of graft rejection that should be decided in certain patients, with certain allograft such as kidney that the possibility of another types of organ replacement therapy dose exist. • J. Haanen et al.ANNAL of Oncology 2020