Very complex, promising research is currently underway to use humanized bispecific single-domain antibodies (bsVHH). But, unfortunately, harnessing the immune system can get very complicated. This article introduces an experimental antibody with a novel approach to fighting CLL / SLL.
These antibodies engage different sub-types of T-lymphocytes to treat chronic lymphocytic leukemia/small lymphocytic leukemia CLL / SLL.
In this study, LAVA-51 bsVHH has been shown to stimulate both type 1 natural killer T cells (NTK) and Vγ9Vδ2-T type T-cells to kill CLL / SLL cells with no off-target toxicity. These two types of T cells have significant killing capacity against malignant B cells, so engaging them makes great sense.
The takeaways below share some of the detailed molecular immunology. Don’t worry if the jargon is overwhelming. The important point is that the researchers are digging deeper to make safer and more effective therapies.
- A molecule called CD1d is highly expressed on B-cell lymphocytes in cancers such as CLL / SLL. Further, inside CLL / SLL cancerous B-cells, phosphoantigens accumulate and express alterations of butyrophilin (BTN) 2A1-3A1 complexes.
- Other subtypes of lymphocytes called T cells can be stimulated to kill tumor cells. For example, the sub-type called Vγ9Vδ2-Tcan detect the BTN 2A1-3A1 alterations within CLL / SLL cells. Further, type 1 natural killer T (NKT) cells recognize tumor cells that express CD1d, which is expressed more on cancerous B cells.
- LAVA-51 is a 27kD bsVHH that has been shown to stabilize the interaction between CD1d and type 1 NKT tumor cell receptor, triggering strong activation of NKT cells. In addition, LAVA-51 also activates the Vδ2-T-cell receptor chain of the Vγ9Vδ2-T type T-cells.
- The activation of NTK and Vγ9Vδ2-T produces cancer cell lysis or death in CLL / SLL and other tumors. This has been demonstrated in vitro (or test tube), ex-vivo, and in-vivo (in live animals).
- LAVA-51 humanized bsVHH cells triggered pro-inflammatory cytokine (inflammatory enzyme) production and proliferation of the B cell killers, specifically Vγ9Vδ2-T and type 1 NKT cells. These effects resulted in the substantial antitumor activity that improved survival in invivo mouse models.
- Fortunately, there were no clinical, laboratory, or histological toxicities.
- Although LAVA-51 bsVHH has a short half-life, it remains bound to the tumor cells for up to 5 days. This, in turn, allows for longer dosing intervals.
- Due to its promising tumor lysis (killing) activity with no toxicity, LAVA-51 bsVHH use has begun the first-in-human Phase1/2a clinical trials in CD1d expressing tumors like CLL / SLL.
We know that T-cell function is often suboptimal in CLL / SLL, limiting the efficacy of CAR-T and other T-cell therapies. Bispecific antibodies are being explored as a way to overcome this weakness. For example, LAVA-51 is pulling together very specific types of T cells that only target CLL cells, thus limiting side effects. In the way of comparison, many other antibodies and immunotherapies target all B cells and induce strong and potentially dangerous inflammatory reactions.
Hope is on the horizon with the development of LAVA-51 bsVHH. This bispecific antibody has successfully stimulated our T-cells to kill cancer cells in CLL / SLL with no toxicity in animal studies. It is now being studied in human trials, with very early results showing good tolerability. However, it is too soon to assess efficacy.
Dr. Alexey Danilov and Dr. Arnon Kater, a hematologist in Amsterdam, and Chairman of the Dutch CLL study group, as they discuss this fascinating research. Dr. Kater does a good job explaining the underlying science and the excitement around his complicated research.
You can read the abstract Bispecific Vγ9Vδ2-T and Type 1 NKT Cell Engager Lava-051 As First-in-Class Clinical Candidate to Target CD1d Expressing CLL, MM, and AML for more details.
Similar research is ongoing, as discussed in the following interview between Dr. Alexey Danilov and Dr. Veronika Bachanova, MD, Professor of Medicine. Please enjoy the interview and read the article, ASH 2021: Off-the-Shelf, Multiplexed-Engineered iPSC-Derived NK Cells Mediate Potent Multi-Antigen Targeting of B-Cell Malignancies with Reduced Cytotoxicity Against Healthy B Cells.
SMART PATIENTS GET SMART CARE™. Be sure to ask your doctor about available, newer, more promising therapies or consider entering a clinical trial.
Stay Strong. We are all in this together.
Michael Green, MD and CLL patient