Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, characterized by an excessive production of immature white blood cells (lymphoblasts) by the bone marrow. Although most children survive ALL, many suffer late or long-term side effects from treatment, including heart problems, growth and development delays, secondary cancers, and infertility. Now researchers at UC Davis and Ionis Pharmaceuticals have developed a new treatment that has the potential to reduce toxicity and secondary effects – an antibody/DNA molecule hybrid that specifically targets ALL cells.
ALL is an acute form of blood cancer, characterized by the overproduction of immature lymphoblasts which multiply and spread to other organs, wasting the resources of the bone marrow that are normally used to produce functioning white and red blood cells. ALL is most common among children aged 2-5 or among the elderly, with around 6,000 new cases and 1,430 deaths from the disease reported every year in the US alone.
Chemotherapy is generally the initial treatment choice, while patients with more advanced disease are often given steroids, radiation therapy, and more intensive treatments, including bone marrow or stem cell transplants.
Treatment is most effective when ALL is diagnosed early. About 80 to 90% of children have a durable complete response following treatment, however long-term side effects of chemotherapy are often reported, highlighting the need for less toxic treatment options.
Can DNA Therapy Reduce Treatment Toxicity?
Antisense oligonucleotides are single strand DNA molecules that can bind to messenger RNA, preventing it from making a protein. Although this technology has a clear therapeutic potential, getting the genetic material inside target cells is still a challenge.
A new study, published in Molecular Medicine has shown for the first time, that a conjugate molecule made up of an antibody and an antisense oligonucleotide can effectively be used as a therapeutic agent for ALL.
In the study, MXD3 was selected as the biological target, as this protein is known to help cancer cells to survive. To silence MXD3, antisense DNA that inhibits the protein was attached to an antibody that binds to CD22, a receptor expressed almost exclusively on ALL cells.
Once the antibody bound to CD22, the leukemia cells internalized the conjugate molecule. Once inside the cell, the antisense DNA molecule prevented MXD3 production therefore triggering cancer cell death.
The efficacy of the hybrid treatment was tested against ALL cell lines in vitro and on primary (patient-derived) ALL cells in a xenograft mouse model. Animals that received the hybrid therapy survived significantly longer than those in the control group.
The treatment was also shown to be selective, exclusively targeting cells that expressed CD22. While healthy B cells were attacked along with leukemia cells, they should be replenished following treatment, with the therapy supposedly leaving blood stem cells and other tissues unharmed.
While the study shows the conjugate is effective in treating animal models of ALL, researchers still need to understand the exact role of MXD3 in the tumorigenic process. Moreover, whether this treatment can be combined with other therapies or can be used against other cancers remain open questions.
To interrogate biological agents and new therapies for ALL predictive preclinical models that present stable disease are needed. Most commercially available models are transient, non-transferable through passages (not renewable), and without disease symptoms and mortality. While they can provide a gross measure of response, they have a finite banked leukemia source from patients.
CrownBio offers a commercially unique collection of patient-derived blood cancer models (HuKemia™), that are validated, stable models with typical disease symptoms and eventual mortality, and that are truly representative of the human condition. Our HuKemia collection includes 19 ALL models, which are well characterized and annotated with expression profiling (U219) and gene copy number data (SNP6). Our ALL collection is also complemented by 6 AML patient-derived HuKemia models, featuring patient relevant mutations.
CrownBio’s permanent HuKemia models allow clients to test the efficacy of novel agents and follow disease recurrence after initial treatment targeting drug resistance. To learn more about our HuKemia models and services contact us today at busdev@crownbio.com
