CAR NK Cell Therapy for T Follicular Helper Cells
Authors: Cecile King
Journal: Cell Reports Medicine (2020)

T follicular helper (TFH) cells are associated with the development of both autoimmune disease and T cell malignancies. In this issue, Reighard et al.,1Reighard S.D. Cranert S.A. Rangel K.M. Ali A. Gyurova I.E. de la Cruz-Lynch A.T. Tuazon J.A. Khodoun M.V. Kottyan L.C. Smith D.F. et al.Therapeutic Targeting of Follicular T Cells with Chimeric Antigen Receptor-Expressing Natural Killer Cells.Cell Rep. Med. 2020; 1 (this issue, 100003-1–100003-10)Google Scholar describe the design of PD-L1 chimeric antigen receptor (CAR) NK cells that effectively target and eliminate TFH cells. T follicular helper (TFH) cells are associated with the development of both autoimmune disease and T cell malignancies. In this issue, Reighard et al.,1Reighard S.D. Cranert S.A. Rangel K.M. Ali A. Gyurova I.E. de la Cruz-Lynch A.T. Tuazon J.A. Khodoun M.V. Kottyan L.C. Smith D.F. et al.Therapeutic Targeting of Follicular T Cells with Chimeric Antigen Receptor-Expressing Natural Killer Cells.Cell Rep. Med. 2020; 1 (this issue, 100003-1–100003-10)Google Scholar describe the design of PD-L1 chimeric antigen receptor (CAR) NK cells that effectively target and eliminate TFH cells. The first CAR T cells were designed and tested in the late 1980s.2Gross G. Waks T. Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.Proc. Natl. Acad. Sci. USA. 1989; 86: 10024-10028Crossref PubMed Scopus (803) Google Scholar The basic premise for the generation of CAR T cells was to use a patient's own T cells, genetically modify them to better recognize and kill cancer cells by expressing a chimeric receptor specific for a particular cancer-associated antigen, and then reinfuse the modified T cells back into the patient. Subsequent studies improved the efficacy of CAR T cell therapy by adding costimulatory signals and cytokine secretion capacity to the cells. These modifications led to CAR-T cell therapy showing some remarkable results in patients.3van der Stegen S.J. Hamieh M. Sadelain M. The pharmacology of second-generation chimeric antigen receptors.Nat. Rev. Drug Discov. 2015; 14: 499-509Crossref PubMed Scopus (240) Google Scholar,4Tokarew N. Ogonek J. Endres S. von Bergwelt-Baildon M. Kobold S. Teaching an old dog new tricks: next-generation CAR T cells.Br. J. Cancer. 2019; 120: 26-37Crossref PubMed Scopus (73) Google Scholar Despite the success of CAR T cells, they do have significant adverse effects that include cytokine release syndrome (CRS) and neurotoxicity. Consequently, research focus increased to genetically modify NK cells with CARs to enhance their known tumor-killing capacity. CAR NK cells have an improved toxicity profile relative to CAR T cells and may make the treatment more accessible to patients. T cells must be genetically matched to individuals to avoid graft versus host disease (GVHD). When the patient's own T cells cannot be used, a complex gene-editing process is required to produce allogeneic CAR T cells. By contrast, there is no such requirement for allogeneic CAR NK cells. CAR NK cells are now actively pursued in a clinical setting. These include the treatment of hematologic malignancies and solid tumors.5Chiossone L. Dumas P.Y. Vienne M. Vivier E. Natural killer cells and other innate lymphoid cells in cancer.Nat. Rev. Immunol. 2018; 18: 671-688Crossref PubMed Scopus (279) Google Scholar,6Miller J.S. Lanier L.L. Natural Killer Cells in Cancer Immunotherapy.Annu. Rev. Cancer Biol. 2019; 3: 77-103Crossref Scopus (50) Google Scholar T follicular helper (TFH) cells interact with B cells to induce the differentiation of B cells that can produce high-affinity antibodies which provide long-term immunity following infection and vaccination.7King C. Tangye S.G. Mackay C.R. T follicular helper (TFH) cells in normal and dysregulated immune responses.Annu. Rev. Immunol. 2008; 26: 741-766Crossref PubMed Scopus (496) Google Scholar,8Vinuesa C.G. Linterman M.A. Yu D. MacLennan I.C. Follicular Helper T Cells.Annu. Rev. Immunol. 2016; 34: 335-368Crossref PubMed Scopus (484) Google Scholar However, dysregulated TFH cells are associated with the development and severity of several autoimmune diseases and T cell malignancies, where the frequency of TFH cells in peripheral blood provides a marker for disease progression. Indeed, the central role of TFH cells in many diseases has made them a major target for therapeutic modulation. The study by Reighard et al.1Reighard S.D. Cranert S.A. Rangel K.M. Ali A. Gyurova I.E. de la Cruz-Lynch A.T. Tuazon J.A. Khodoun M.V. Kottyan L.C. Smith D.F. et al.Therapeutic Targeting of Follicular T Cells with Chimeric Antigen Receptor-Expressing Natural Killer Cells.Cell Rep. Med. 2020; 1 (this issue, 100003-1–100003-10)Google Scholar provides evidence supporting the use of CAR NK cells to reduce the load of PD-1-expressing TFH cells in human disease. The approach described effectively reduced or eliminated TFH cells in peripheral blood, providing exciting proof-of-principle evidence for the use of CAR NK cells in TFH-driven diseases. PD-L1 expressing CAR NK-92 cells were designed, and generated, and observed to degranulate in response to ligand and Raji human B cell lymphoma cells that have been engineered to express high levels of human PD-1, but not in the absence of PD-1 expression on target cells. Co-culture of CAR NK-92 cells with human tonsillar CD4+ cells resulted in a 7-fold reduction in CXCR5+ PD-1+ TFH cells. By contrast, co-culture of control NK-92 cells and tonsillar CD4+ T cells had no such effect on TFH cells. Since T follicular regulatory (TFR) cells express very high amounts of cell-surface PD-1, it was curious to observe that CAR-NK cells had less effect on TFR cells than TFH cells. Nevertheless, the addition of CAR-NK cells, but not NK cells, to 3 day SEB-stimulated tonsillar CD4+ CXCR5+ T and CD27+ B cell co-cultures reduced both B cell proliferation and antibody production, indicating that TFH cell elimination had the dominant effect on B cell function in this setting. To test the effect of CAR NK-92 cells in vivo, a humanized mouse model of lupus-like disease was generated by reconstitution with cord blood leukocytes prior to pristane injection. The resulting mice exhibit elevated antibody production, PD-1+ CD4+ T cells, and splenomegaly. Treatment of these mice with CAR NK-92 cells reduced both the splenomegaly and the numbers of CD4+ T cells, with a proportionally greater loss of CD4+ T cells expressing high amounts of PD-1. Following infusion, CAR-NK-92 cells were found in the spleen and liver of recipient humanized mice. However, for TFH cell depletion to therapeutically modify autoimmune disease, CAR NK cells may have to gain access to follicular tissues, germinal centers, and ectopic GCs. Future studies for clinical application will need to test this promising strategy on primary human cells and to validate the migration of CAR-NK cells into these important target sites, which may require further modifications. Therapeutic Targeting of Follicular T Cells with Chimeric Antigen Receptor-Expressing Natural Killer CellsReighard et al.Cell Reports MedicineMarch 25, 2020In BriefExaggerated follicular helper T cell (TFH) responses promote autoimmunity and other pathologies, yet clinical tools to specifically target TFH are lacking. Reighard et al. describe programmed death-ligand 1 (PD-L1)-based chimeric antigen receptor-expressing human natural killer cells that selectively eliminate human TFH in vitro and in humanized mice based on the high expression of PD-1 by the targeted TFH cells. Full-Text PDF Open Access