External News Items

CD20-directed immunotherapy resistance partially explained

Researchers have reported new insights into the mechanisms of how B-cell cancers become resistant to CD20-targeting immunotherapies, offering hopes of improving survival."

5′-UTR mRNA splicing determines CD20 levels

In this issue of Blood, Ang et al show that human CD20 messenger RNA (mRNA) undergoes alternative splicing to generate distinct 5' untranslated region (5'-UTR) variants, which determine the cell-surface CD20 levels in malignant B cells and the interpatient variability in the expression of this therapeutic target. These variants can also be used as an escape mechanism from anti-CD20 therapies... more than 30 years after the work by Tedder et al, this study deciphered the effect of MS4A1 mRNA isoforms on this mRNA's translation efficacy." - Dr. Marek Mraz

Read more in Blood Commentary

Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy

Our original study of the epitope loss taught us a valuable lesson that genomic sequencing often does not tell the whole story, and that post-transcriptional regulation such as alternative splicing can be a potent driver of resistance to immunotherapy." - Elena Sotillo, PhD, Stanford University, and Andrei Thomas-Tikhonenko, PhD, Children's Hospital of Pennsylvania and University of Pennsylvania

Read more in Cancer Discovery Q&A

The Pediatric Immunotherapy Discovery and Development Network (PI-DDN)

This collaborative network is identifying and advancing preclinical immunotherapy research for children and adolescents with cancer. The network is working to discover and characterize new targets for immunotherapies, design experimental models to test the effectiveness of pediatric immunotherapies, develop new pediatric immunotherapy treatments, and improve the understanding of tumor immunity in children and adolescents with cancer. PI-DDN is also working to overcome major barriers in developing effective immunotherapies for children and adolescents, such as lower levels of proteins in tumor cells that can be recognized by immune cells and the immunosuppressive environments of tumors in some pediatric cancers... Investigators in the PI-DDN are working together on multicomponent research studies centered around a pediatric cancer research area and individual pediatric immunotherapy projects. The goal of the network is to advance pediatric immunotherapies to treat children and adolescents with high-risk cancers."

CureSearch Acceleration Initiative Award: 2022-2025

We have been working for several years to determine whether messenger RNAs pervasively mis-spliced in cancer cells give rise to aberrant protein isoforms, and whether these isoforms can be found on cell surface and targeted with a new generation of immunotherapeutics. Just last year we generated a first-in-class antibody specific for the mis-spliced CD22 surface marker commonly found in B-lymphoblastic leukemia. Now we aspire to extend this target discovery pipeline to some of the deadliest pediatric cancers: high-grade gliomas and neuroblastomas. They originate, respectively, in the central and peripheral nervous systems and share most surface markers with normal neurons. This makes the development of immunotherapeutic challenging, but we hope that our novel strategy will overcome traditional obstacles.” - Dr. Andrei Thomas-Tikhonenko

Meet Dr. Thomas-Tikhonenko: Childhood Cancer Research | Scientist Spotlight

Research Project funded by Cookies for Kids’ Cancer:
Novel chemoimmunotherapeutics for B-lymphoid childhood malignancies.

In layman’s terms, what is the purpose of the research project?
To develop new antibodies capable of killing leukemic cells but sparing normal white blood cells."

V Foundation Grant Award

Over the past several decades, there has been a steady increase in cure rates in children with the so- called B-cell acute lymphoblastic leukemia (B-ALL), a type of blood cancer. Yet many B-ALL patients who failed the initial chemotherapy still die from their disease. Five years ago many of these high-risk patients began to benefit from immunotherapy, whereby patients’ own immune systems are trained to recognize and destroy the leukemic cells. One common form of immunotherapy is based on recognition of CD19, a protein residing on the surface of most leukemic cells. However, even this breakthrough treatment fails in about a third of patients, suggesting that other leukemia proteins need to be targeted in parallel. One alternative protein target is called CD22. CD22-directed immunotherapies show promise, but are not without their own record of failures. Our previous studies led us to believe that one common cause of treatment failure is improper assembly of the CD22 protein, resulting in re-shuffling of its key parts called ectodomains. This re-shuffling could result in CD22 becoming unrecognizable to the immune system. On the other hand, improperly assembled CD22 could be targeted using a new type of immunotherapeutics, which are trained to recognize improper junctions between ectodomains. The proposed work will test these ideas using leukemic cells grown in Petri dishes and in mice and samples from ongoing clinical trials. It will also extend our current studies to other cell surface proteins. In the end, the TVF-funded work would lead to a more precise matching of future patients to best possible treatments and thus much better outcomes."