Page 33 - 2021_09-Haematologica-web

Targeting the tumor microenvironment in CLL
Through their potent activation of T cells, CELMoD and IMiD could represent strong complementary treatment partners for combination (immune)therapy.14,15,73,75,76,80,81 It has been demonstrated preclinically that the CELMoD avadomide could sensitize CLL to anti-PD-1 or anti-PD-L1 immunotherapy.81 By inducing inflammatory interferon type I and II signaling in previously exhausted T cells from patients, avadomide stimulated the proliferation and release of chemokines by T cells which recruited addition- al CD8+ T cells, upregulated PD-L1 in the immune TME, and enhanced lytic synapse formation.81
Even more powerful combinations could include pair- ing ICB with CAR T cells or bispecific antibodies to increase tumor infiltrating T cells, or dual ICB combina- tions to overcome additional inhibitory barriers. T-cell bispecific antibodies combined with an anti-PD-L1 anti- body showed enhanced antitumor efficacy compared to either given alone in a solid cancer mouse model.105 Furthermore, a recent CLL murine study demonstrated that anti-PD1 ICB combined with inhibition of the immune checkpoint receptor lymphocyte-antigen gene 3 (LAG3) was able to decrease tumor load significantly, while either as monotherapy had little effect.106
Thus, developing combination immunotherapy could represent a powerful strategy for deepening targeted drug (e.g., BTK inhibitor- and/or venetoclax)-induced respons- es and working towards curative therapy in CLL.
Future perspectives: novel targetable tumor microenvironment interactions
The CLL-TME constitutes a landscape of potential tar- getable pathways. Antibodies interrupting the CXCL12/CXCR4 interaction have demonstrated anti-CLL activity in vitro and in mouse models, and have been tested in phase I clinical trials for multiple myeloma, but have not yet been further explored in CLL.107 The BAFF/BAFF-R axis constitutes another attractive CLL-TME interaction to target. An anti-BAFF-R antibody blocked protective sur- vival signaling in CLL cells and enhanced antibody-depen- dent cellular cytotoxicity in vitro, and also enhanced effica- cy of ibrutinib in a CLL mouse model.108 Targeting of an IL- 10-producing CD38hi regulatory B cell-like CLL subset is also currently under investigation.27 Although aimed at CLL cells, the anti-leukemic potential here would be mediated indirectly by abrogating IL-10-mediated immuno- suppression. The “don’t eat me” signal regulatory protein (SIRP)1α/CD47 axis, co-expressed by macrophages and malignant cells, respectively, in various lymphoid malig- nancies including CLL, constitutes a mechanism of
myeloid immune tolerance. It is currently being explored as a potential target in lymphoma, and may also constitute an important macrophage-CLL interaction with targetable potential.109 Furthermore, MDSC-derived indoleamine 2,3- dioxygenase (IDO) has been explored as a target in other cancers, as an antitumor vaccination antigen.110 Mediating strong immunosuppressive effects in the CLL-TME, IDO may constitute another potentially attractive interaction to target in CLL.
In conclusion, the heterogeneous course of CLL is driv- en by (i) the genetic complexity and (ii) diverse and com- plex tissue TME interactions, including (iii) antigenic drive. The functionally and phenotypically skewed cell types within the TME not only promote CLL itself, but also compromise the induction of adequate immune responses towards developing and progressing CLL clones, as well as infectious agents. Thus, further explo- ration of the impact of different therapies on critical microenvironmental interactions is warranted. This review was intended to outline our current understanding of how CLL-TME interactions are influenced by current CLL therapies, with the view to encourage continued mapping of the CLL-TME for more specific future target- ing of CLL-TME crosstalk. The inclusion of translational correlative studies assessing immunological and TME changes within clinical trials should inform development of novel combination therapies beyond BTK inhibitors and BCL-2 inhibitors. These include, but are not limited to, checkpoint inhibitors, T-cell based therapies, and TME modulation overcoming the inherent immune exhaustion in CLL. Such strategies together with further understand- ing of the TME should, eventually, lead to improved and more personalized treatment options aiming for a clinical cure with reduced burden of adverse events for patients with CLL.
Disclosures
None of the authors received funds or any other direct contri- bution to support the submitted work. There are no patents or copyrights relevant to this work. RS received research support from AstraZeneca, and travel grants from Abbvie outside of this work. CN received research support and/or personal consultancy fees from Abbvie, AstraZeneca, Janssen, Roche, Danish Cancer Society and Novo Nordisk Foundation (grant NNF16OC0019302) outside of this work. SJ, AR and PP have no conflicts of interest to disclose.
Contributions
RS and SJ wrote the first draft of the review under supervision of CN; the final version of the review was written by all five authors. All authors approved the final version.
References
1. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol. 2019;94(11):1266-1287.
2. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B- cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563-574.
3. Burger JA, Ghia P, Rosenwald A, Caligaris- Cappio F. The microenvironment in mature
B-cell malignancies: a target for new treat- ment strategies. Blood. 2009;114(16):3367- 3375.
4. Dubois N, Crompot E, Meuleman N, Bron D, Lagneaux L, Stamatopoulos B. Importance of crosstalk between chronic lymphocytic leukemia cells and the stromal microenvironment: direct contact, soluble factors, and extracellular vesicles. Front Oncol. 2020;10:1-19.
5. Caligaris-Cappio F, Bertilaccio MTS, Scielzo C. How the microenvironment wires the natural history of chronic lymphocytic
leukemia. Semin Cancer Biol. 2014;24:43-
48.
6.George B, Chowdhury SM, Hart A, et al.
Ibrutinib resistance mechanisms and treat- ment strategies for B-cell lymphomas. Cancers (Basel). 2020;12(5):1328.
7. Boissard F, Fournié JJ, Quillet-Mary A, Ysebaert L, Poupot M. Nurse-like cells medi- ate ibrutinib resistance in chronic lympho- cytic leukemia patients. Blood Cancer J. 2015;5(10):e355.
8. Chen JG, Liu X, Munshi M, et al. BTK Cys481Ser drives ibrutinib resistance via
haematologica | 2021; 106(9)
2321