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R.A.L. de Groen et al.
Figure 3. Schematic representation of the potential use of liquid biopsies during disease progression in B-cell non-Hodgkin lymphoma. After diagnosis, a hypothet- ical patient was treated with immune-chemotherapy. During therapy, the lymphoma was significantly reduced, as evidenced by a complete metabolic remission on positron emission tomography-computed tomography (PET/CT) scans and minimal residual disease by the analysis of circulating tumor DNA (ctDNA) mutation fre- quency. Thereafter, the residual B-cell lymphoma developed again, gradually increased, and induced a significant clinical relapse. Following comprehensive (genetic) diagnostic procedures, including histological confirmation, liquid biopsies, and PET/CT scans, the patient was treated with BTK inhibition as a second-line therapy, consequently reducing the lymphoma and leading to a partial metabolic remission. Lastly, residual lymphoma cells harboring a BTK(C481S) mutation gained resist- ance to the BTK inhibition therapy; these cells expanded unimpeded and resulted in another clinical relapse. In this schematic representation, the mutation frequen- cy throughout the course of the patient’s disease is plotted. The two detection limits indicate the sensitivity of PET/CT and the liquid biopsy (e.g., ctDNA with digital droplet polymerase chain reaction analysis).
comes.129 In in vitro assays, enzastaurin, a protein kinase C inhibitor, reduced proliferation and viability of DLBCL cells by regulation of the PI3K, MAPK, and JAK/STAT pathways; however, it also increased phosphorylation of BTK, suggesting the need for simultaneous treatment of enzastaurin with BTK inhibition.130 Patients with DLBCL are currently being recruited into a phase III clinical trial in which enzastaurin is combined with R-CHOP (NCT03263026).
The clinical trials mentioned above focus on therapeutic targets that are directly or indirectly involved with MYD88 activity; however these targets are not specific for MYD88(L265P) and patients are selected irrespective of the mutational status of MYD88. The lack of biomarkers in these clinical trials is a potential weakness, especially regarding the evolving field of genetics and precision medi- cine. Novel drugs targeting the oncogenic mechanisms of MYD88(L265P), such as inhibition of the interaction between TLR9 and MYD88 in the My-T-BCR supercom- plex8 and between MYD88 and IRAK4 in the myddo- some,131 or direct inhibition of IRAK411,39 or TAK1,7 would be interesting for B-NHL patients with MYD88(L265P) and have shown promising results in in vitro and in vivo studies. In addition, the use of immunomodulatory oligonu- cleotides (IMO) such as IMO 8400, an antagonist of TLR7, TLR8, and TLR9, could be an interesting targeted treatment for MYD88(L265P) B-NHL and especially for ABC-DLBCL
with the My-T-BCR supercomplex. IMO-8400 has mainly been investigated in immune-mediated inflammatory dis- eases and only two phase I/II clinical trials with MYD88(L265P)-positive DLBCL and WM have been per- formed, showing that IMO-8400 is well tolerated in these patients (NCT02252146, NCT02363439, https://www.ider- apharma.com/wp-content/uploads/2015/12/IMO-8400-WM- ASH-Poster.pdf). More research is required on the MYD88(L265P)-specificity of the above-mentioned targets in order to determine their role in the treatment of B-NHL patients with MYD88(L265P) and, thereby, improve per- sonalizedmedicine.
An alternative therapeutic approach for these patients, as reviewed by Weber et al.,119 is the induction of a T-cell mediated immune response towards tumor-specific neoepitopes that are derived from MYD88(L265P). In in vitro experiments, such neoepitopes, presented by major histocompatibility class I molecules, prompted a cytotox- ic CD8+ T-cell response.132 These tumor-specific T cells can be harvested from healthy donors133 or patients with B-NHL and primed to elicit a tumor-specific cytotoxic effect or theoretically used as a model for chimeric anti- gen receptor (CAR) T-cell therapy. Furthermore, in vitro assays of DLBCL showed that MYD88(L265P) tumor cells develop resistance against T-cell mediated cytotoxicity via upregulation of IL-10 and STAT3 and that inhibition of either IL-10 or STAT3 significantly attenuates this gain
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haematologica | 2019; 104(12)