Regulatory T Cells in CLL: Immune System Exhaustion and Potential Restoration, and the Role of Immuno-Oncology Therapies

Sep 2, 2021 1:00:00 PM / by Champions Oncology

3D rendering of T cells attacking cancer cells

Chronic lymphocytic leukemia (CLL) is one of the most commonly occurring hematologic malignances with no known cure and is defined by the clonal expansion and accumulation of CD5+ B cells in the blood and bone marrow. Standard treatments to manage disease include chemotherapy and rituximab (anti-CD20 monoclonal antibody). Newer therapies that are less prone to resistance or treatment failure are currently being examined, such as Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 biosimilars[1],[2].

T cells play a critical role in anti-tumor responses, but CLL patients typically have CD4+ and CD8+ T cells with functional and phenotypic changes consistent with exhaustion that is likely to limit their efficacy[3]. Untreated CLL patients commonly have elevated levels of regulatory T cells (Tregs) in peripheral blood, and this increase in Tregs can cause immune suppression and allow malignant CLL blasts to proliferate as anti-tumor immune responses are suppressed[4]. Phenotypic characterization of T cells provides critical insights into the potential efficacy of different immuno-oncology treatments, as recently described in a study that identified T cell signatures associated with the efficacy of chimeric antigen receptor (CAR) T cell-based treatment of CLL[5].

Venet_Horiz_Final

Champions Internal data collected from the CLL VitroScreen evaluating Venetoclax treatment ex vivo

Newly developed immuno-oncology therapies can reverse immune suppression and restore T cell functions. Treatment with BTK inhibitors such as ibrutinib have been shown to improve cytotoxic T cell functions, suppress Tregs, decrease immune checkpoint molecule expression and restore cytokine responses[6],[7],[8]. Ibrutinib also appears to attenuate the inflammatory environment in the bone marrow that allows CLL B cells to suppress antitumor responses[9]. Together these effects can restore T cell function and improve antitumor responses to CLL, especially relapsed or refractory (R/R) CLL. Venetoclax is another recently licensed R/R CLL treatment that inhibits the function of the antiapoptotic protein B cell lymphoma 2 (Bcl2), which is constitutively expressed in CLL cells and causes resistance to apoptotic cell death[10]. Venetoclax is a highly selective inhibitor that can induce apoptosis in CLL and reduce immunosuppression and can be combined with other immune-oncology treatments. Pevonedistat is a first-in-class Nedd8-activating enzyme inhibitor that can sensitize CLL cells to death-receptor mediated apoptosis[11] and has been given a Breakthrough Therapy Designation for the treatment of higher-risk myelodysplastic syndromes, like CLL, in combination with other chemotherapeutics[12].

These recent breakthroughs in immuno-oncology development highlight the importance of functional T cell responses and the flexibility of the immune system that allows for such responses to be restored, even under chronic immunosuppression.

 

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[2] Burger JA, O’Brien S. Evolution of CLL treatment—from chemoimmunotherapy to targeted and individualized therapy. Nature Reviews Clinical Oncology. 2018. 15(8), 510-527.

[3] Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121(9):1612-1621.

[4] De Matteis S, Molinari C, Abbati G, et al. Immunosuppressive Treg cells acquire the phenotype of effector-T cells in chronic lymphocytic leukemia patients. J. Transl. Med. 2018;16(1):172.

[5] Fraietta, Joseph A., et al. "Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia." Nature Medicine 24.5 (2018): 563-571.

[6] M. Long, K. Beckwith, P. Do, B.L. Mundy, A. Gordon, A.M. Lehman, K.J. Maddocks, C. Cheney, J.A. Jones, J.M. Flynn, L.A. Andritsos, F. Awan, J.A. Fraietta, C.H. June, M.V. Maus, J.A. Woyach, M.A. Caligiuri, A.J. Johnson, N. Muthusamy, J.C. Byrd. Ibrutinib treatment improves T cell number and function in CLL patients. J. Clin. Invest., 127 (8) (2017), pp. 3052-3064.

[7] K. Kondo, J.A. Burger, K. Micheal, J. Tran, M. Muftuoglu, M. Daher, H. Shaim, P. Thompson, N. Imahashi, A. Alsuliman, W. Wierda, E. Liu, E.J. Shpall, K. Rezvani. Ibrutinib can modulate the T cell response in chronic lymphocytic leukemia by reducing PD1/PDL1 interactions. Blood. 126 (23) (2015), p. 1737.

[8] H.M. Parry, N. Mirajkar, N. Cutmore, J. Zuo, H. Long, M. Kwok, C. Oldrieve, C. Hudson, T. Stankovic, S. Paneesha, M. Kelly, J. Begum, T. McSkeane, G. Pratt, P. Moss. Long-term ibrutinib therapy reverses CD8(+) T cell exhaustion in B cell chronic lymphocytic leukaemia. Front. Immunol., 10 (2019), p. 2832.

[9] P. Bachireddy, C.J. Wu. Arresting the inflammatory drive of chronic lymphocytic leukemia with ibrutinib. Clin. Cancer Res., 22 (7) (2016), pp. 1547-1549.

[10] de Weerdt I, Hofland T, de Boer R, et al. Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment. Blood Adv. 2019;3(17):2642-2652.

[11] Paiva C, Godbersen JC, Rowland T, Danilova OV, Danes C, Berger A, Danilov AV. Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis. Oncotarget. 2017 Mar 28;8(13):21128-21139.

[12] https://www.takeda.com/newsroom/newsreleases/2020/takeda-announces-u.s.-fda-breakthrough-therapy-designation-granted-for-pevonedistat-for-the-treatment-of-patients-with-higher-risk-myelodysplastic-syndromes-hr-mds/.

Tags: Immuno-Oncology, Hematological Malignancies