CLL Treatments Take Aim at Targeting Tumor Microenvironment

According to the researchers, attempting to target the tumor microenvironment leads the way to an array of potential targetable pathways in the disease, including through the use of combination therapy.

A variety of treatments spanning different treatment classes are being studied for use in chronic lymphocytic leukemia (CLL) in an attempt to target the tumor microenvironment environment (TME) of CLL, which attributes to the disease’s genetic complexity. In a recent review, researchers outlined the potential of the approach.

According to the researchers, attempting to target the TME, which is essential for the development, growth, and survival of malignant B-cell clone in CLL, leads the way to an array of potential targetable pathways in the disease, including through the use of combination therapy.

“It is becoming evident that improving clinical responses (residual and progressive disease), overcoming toxicity, infection risk, as well as drug resistance, likely require strategies aimed at reshaping the immunosubversive, pro-tumor TME state,” explained the researchers. “Our improved understanding of the direct and indirect CLL-TME modulations by novel therapeutic agents in recent years provides a unique opportunity to optimize CLL treatment with strategic drug combinations that target multiple CLL-TME interactions to achieve therapeutic synergy while controlling toxicity.”

Combinations include adding venetoclax to ibrutinib, which has showed promise for improving the duration of remissions, as well as adding the PI3K inhibitor duvelisib to venetoclax to improve the sensitivity of CLL cells. The latter is currently being tested in clinical trials.

Venetoclax has also showed promise in combination with anti-CD20 antibodies, with the combination demonstrating in vitro an improvement in the phagocytosis of CLL cells by macrophages while reversing resistance to venetoclax.

“Interestingly, although venetoclax plus anti-CD20 treatment produces impressive clinical responses in clinical trials, a recent retrospective study including real-world data demonstrated comparable efficacy between venetoclax as a single agent and venetoclax plus anti-CD20 combination treatment in high risk relapsed/refractory CLL patients,” wrote the researchers, “Thus, further validating prospective studies are warranted to determine whether the addition of an anti-CD20 antibody to venetoclax is truly necessary.”

On the other hand, adding an anti-CD20 antibody to ibrutinib also seemed to result in faster remissions and lower residual disease but was found to not improve profession-free survival.

Research has also focused on chimeric antigen receptor (CAR) T-cell therapy, as identifying treatment regimens that overcome T-cell dysfunction and improve the efficacy of T-cell-based treatments and immune checkpoint blockade represent some of the biggest challenges in CLL.

Early research has indicated that adding ibrutinib to CAR T-cell function concurrently may enhance CAR T-cell function. In one clinical pilot study, adding concurrent ibrutinib to CD19-targeted CAR T-cell therapy showed strong response rates in patients with relapsed/refractory CLL. The treatment combination also showed lower toxicities than CAR T-cell therapy alone.

Reference

Svanberg R, Janum S, Patten P, Ramsay A, Niemann C. Targeting the tumor microenvironment in chronic lymphocytic leukemia. Haematologica. Published online April 22, 2021. doi:10.3324/haematol.2020.268037