Idelalisib demonstrates a dual mechanism of action by inhibi
Idelalisib demonstrates a dual mechanism of action by inhibiting pro-survival signalling pathways , and, like other kinase inhibitors, leads to re-localisation of tumour Schindler list by blocking ingress into and promoting egress out of the lymph node into the blood. Release from the protective lymph environment into blood renders CLL cells more susceptible to apoptosis. PI3Kδ is expressed by all leucocytes including T cells, raising the possibility that the therapeutic effect of idelalisib may, at least in part, be due to effects on the surrounding immune cells in addition to direct effects on CLL cells . Intriguingly, IL-4 protects against idelalisib induced apoptosis in vitro , indicating that microenvironmental influences may protect CLL cells against PI3K inhibitors and that co-inhibition of the function of surrounding cells may be an important factor in successful treatment.
Ongoing clinical trials with idelalisib are examining the combination with other agents; including rituximab, ofatumumab, obinutuzumab and bendamustine. Furthermore, a recent publication showed that combination of idelalisib with ibrutinib is synergistic, indicating potential benefit from combined or sequential therapy . In addition to idelalisib, development of other PI3Kδ inhibitors for the treatment of lymphoid malignancies is ongoing including TGR-1202, a novel PI3Kδ inhibitor with significant differences in its chemical structure compared to idelalisib and with lower reported incidences of colitis in patients. TGR-1202 is currently in phase I clinical trials, with significant nodal responses observed in 88% of relapsed/refractory CLL patients to date (clinicaltrials.gov, NCT01767766).
Duvelisib (IPI-145) targets both PI3Kδ and PI3Kγ isoforms  and induced apoptosis in CLL samples in vitro, abrogated bone marrow stromal cell-mediated survival, inhibited BCR mediated signalling and chemotaxis in response to CXCL12 . Importantly, duvelisib also killed CLL cells that were resistant to ibrutinib , this may hold true with other PI3K inhibitors, and could form an important strategy for treating patients refractory to ibrutinib. Duvelisib has completed phase I clinical trials in which 89% of patients showed a reduction (≥50%) of enlarged lymph nodes and 47% patients showed an overall response to the drug . Duvelisib is now in a number of clinical trials for CLL, including in combination with anti-CD20 antibodies and in patients refractory to ibrutinib (clinicaltrials.gov, NCT02292225, NCT01871675).
Although these results are extremely promising, the long term effects of PI3Kδ inhibition in patients are unknown. Will the disruption of regulatory T cell function over a number of years lead to increased risk of developing autoimmune disorders? Furthermore, increased incidences of colitis have been reported in patients treated with idelalisib, and although the exact cause is unknown, increased colitis also occurred in a murine model where PI3Kδ kinase activity was disrupted. Moreover, the PI3Kδ isoform is expressed by epithelial cells and is known to have a crucial role in lumen formation . This challenges the concept of restricted usage of PI3Kδ to haematological cells and therefore raises potential concerns for the effect of PI3Kδ inhibitors on epithelial tissues; however patient responses to these agents in the short term may outweigh any potential long term effects.
Potential therapeutic use of PI3Kα and/or pan-PI3K inhibitors in CLL PI3Kδ has been the overwhelming target of choice for PI3K inhibition in CLL; however there is mounting evidence for important roles of other PI3K isoforms in CLL and of functional redundancy between PI3K isoforms in leucocytes in general . Amplification of the PIK3CA locus which encodes for the PI3Kα catalytic subunit has been identified in a proportion of CLL patients  and may contribute to constitutive PI3K activation in a subset of CLL patients. In normal B cells either PI3Kα or PI3Kδ can mediate tonic BCR signalling and low level AKT phosphorylation, with PI3Kα able to compensate for the absence of PI3Kδ and maintain normal B cell development in the bone marrow . In contrast, agonist-induced AKT phosphorylation is solely PI3Kδ mediated . Given that BCR derived signalling is crucial for CLL pathogenesis, the inhibition of both PI3Kα and PI3Kδ may be superior to inhibition of either isoform alone and may overcome any functional redundancy between isoforms. Interestingly, constitutive PI3Kα activity limited the efficacy of idelalisib in mantle cell lymphoma and the combined inhibition of both PI3Kα and PI3Kδ was required to abrogate constitutive AKT phosphorylation .