Checkpoint Inhibitors - the Programmed Death 1 and Ligand (PD-1/PD-L1) checkpoints and their promise for CLL/SLL

[AussieNeil]

In the last few years, we've seen amazing advances in the approvals of safer, more effective non chemo treatments for CLL/SLL. That momentum doesn't look as if it will stop any time soon, which is a huge improvement on the situation of just a few years ago, when FCR was the only improved treatment to come out of a veritable desert of years with nothing much happening. The latest treatment 'buzz word' is Checkpoint Inhibitors and the Cancer Network (free membership) has a couple of articles relevant to us on these new cancer killing targets. Basically researchers have found a way of disrupting the way cancer cells turn off our immune system to protect themselves. As the second article says " immune checkpoints (are) key elements in the physiologic process that limits autoimmunity in the normal host but that also limits immune surveillance in cancer."

"The anti-CD20 antibody rituximab, the first monoclonal antibody approved for treating cancer, revolutionized the therapy of B-cell lymphomas in 1997. Recently, a new set of antibodies—this time targeting the immune regulatory “checkpoints” cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1)—have created a stir in the treatment of numerous solid tumors. Thankfully, this approach has now moved into the hematologic cancer arena, adding another weapon to the growing arsenal of nonchemotherapy agents available to treat lymphomas, myeloma, and leukemias." including CLL and SLL!

More detail in these articles:

Hematologic Cancers Break Down a ‘Checkpoint’: Targeting the PD-1/PD-L1 Axis (The overview)

cancernetwork.com/oncology-...

It's encouraging to read that "PD-L1... expression was most prominent in the subset of diffuse large B-cell lymphomas with the “activated B cell” phenotype that carries a poorer prognosis."

Note also that "Critically, they also point out that because PD-1 blockade works by reawakening T cells to attack tumors, concurrent combination therapy with conventional cytotoxic chemotherapeutics might actually negate the beneficial effects, and the sequencing and timing of therapies may thus be crucial to achieving optimal efficacy."

Releasing the Brake on the Immune System: The PD-1 Strategy for Hematologic Malignancies (A review article on the fast-evolving use of anti–PD-1/PD-L1 antibodies in the treatment of hematologic malignancies)

cancernetwork.com/oncology-...

As the overview article concludes: "it is clear that research involving the immunotherapy of blood cancers is moving swiftly through this first “checkpoint” at breakneck speed. It is sure to be a fascinating ride."

Neil

[Calopteryx]

Thanks for this Neil. Great to know there are further strides being made in potential treatments.

[wassupdoc]

Tacking this one on to your thread Neil... Same topic new article:

bloodjournal.org/content/12...

Excerpted:

"As PD-L1 blockade directly after transfer could not prevent CLL engraftment in the spleen, the impact of giving such inhibitors as monotherapy after full development of leukemia may be limited. The impact of giving such inhibitors after full development of leukemia may therefore be limited.

One such combination therapy could be the use of inhibitors of BCR signaling, such as PI3-kinase inhibitors or Bruton tyrosine kinase (BTK) inhibitors. By inhibition of BCR-mediated adhesion and migration to the lymph node, these agents inhibit the intimate cross-talk between CLL and immune effector cells. In addition, the BTK inhibitor ibrutinib also inhibits interleukin-2–inducible kinase, resulting in T-helper 1 skewing.11 Studies in mouse models indicate synergistic activity of these two classes of agents.12 Another strategy to potentiate the efficacy of immune checkpoint inhibitors might be combination with immune modulatory agents such as lenalidomide. Lenalidomide increases expansion and T-cell effector function in the context of CLL. These effects of lenalidomide have been attributed to downregulation of expression of both PD-L1 on tumor cells and PD-1 on T cells.13 The use of two drugs that both target PD-1/PD-L1 signaling could potentially increase the efficacy of therapy."

[Cllcanada Top Poster CURE Hero]

Dr. Jeff Sharman is currently running a Phase1 trial using ACP-196

(like ibrutinib) and pembrolizumab, a PD-1/PD-L1 inhibitor...

~chris