Researchers at The University of Manchester have discovered that 5T4, a transmembrane glycoprotein overexpressed by a variety of cancers and correlated with increased invasiveness, contributes to chemotherapy resistance in the most common type of childhood leukemia. Using a novel approach, early testing shows that targeting the protein with an antibody-drug conjugates or ADC could hold great promise in improving treatment.
The research, which was funded by the blood cancer charity, Bloodwise, is published in Haematologica. [1]
Survival rates for childhood acute lymphoblastic leukemia or ALL have improved substantially over the years. On average, around nine in 10 children can be treated – and cured of the disease. However, but current treatment options include an intense, gruelling, course of chemotherapy which may leave children with life-long side effects such as infertility and potentially secondary cancers. There is also a chance of the blood cancer returning if high levels of leukemia initiating cells remain after the first rounds of intensive treatment. If the cancer comes back, it is more difficult to treat.
In a study led by Vaskar Saha, MD, Ph.D, Professor of Pediatric Oncology at The University of Manchester and Peter Stern, MD, Ph.D, Professor in Immunology, analyzed samples from children who were determined to be at either low or high risk of relapse based on the numbers of leukaemic cells remaining after their first round of chemotherapy.
The researchers found a high proportion of 5T4 positive leukemia cells in patients with a high risk of relapse, while this marker was not detected in samples taken from children who responded well to initial treatment.
5T4 positive leukemia cells are significantly more clonogenic. This means that the disease can recur from very few residual cells. The researchers discovered that the 5T4 protein helps leukemia stem cells migrate from the blood vessels to the safety of the bone marrow during treatment, which makes these cells much harder to eradicate as this offers protection from chemotherapy.
Novel treatment option
Using a model system of human leukemia engrafted in mice, an ADC developed by Pfizer Inc., A1mcMMAF (5T4-Antibody Drug conjugate), also known as PF 06263507, which targets cells with 5T4 molecules on the surface and delivers a drug which is toxic for the cells, was shown to be very effective in treatment and significantly improved survival without overt toxicity. In addition, when used in combination with dexamethasone, a standard component of induction therapy, there was a significantly improved survival of the mice.
In their paper, the researchers confirmed that the sequential administration of dexamethasone and A1mcMMAF significantly improved survival (p=0.0006) over either monotherapy.
The antibody-drug conjugate PF-06263507 is composed of an antibody directed against 5T4 and conjugated, via the stable linker maleimidocaproyl (mc), to the microtubule inhibitor monomethyl auristatin phenylalanine (MMAF). Following administration, the antibody moiety selectively binds to cells expressing the 5T4 oncofetal antigen. Then, after internalization and enzymatic cleavage of the immunoconjugate within the tumor cell cytosol, free MMAF binds to tubulin and inhibits its polymerization, which result in G2/M phase arrest and tumor cell apoptosis.
“Although this is early work, our findings suggest that leukaemic initiating cells that have 5T4 are better at entering sites in the body that will protect them from standard chemotherapy, causing drug resistance and relapse,” Vaskar Saha said.
“By targeting 5T4 in mice, we have shown that we can selectively attack the treatment-resistant leukaemia cells,” Saha added.
Importance of early findings
“The chemotherapy currently used to treat childhood ALL is not always effective, and can cause life-long side effects. Using targeted therapies – alone or in combination – that hone in on specific characteristics of the cancer cells, could eventually make therapies gentler and more effective. These early findings are promising, and have opened up the future possibility of a new targeted treatment for childhood ALL,” noted Alasdair Rankin, MD, Director of Research at Bloodwise.
Clinical trial: A Study Of PF-06263507 In Patients With Advanced Solid Tumors (NCT01891669)
