“Fundamentally, there is a huge difference between the treatment of childhood and adult cancers and any novel treatment developed for pediatric oncology needs to recognize that,” starts Timothy Triche, M.D., Ph.D., Co-Director of the Children’s Hospital Los Angeles (CHLA) Center for Personalized Medicine Program, in an edited interview for The Onco’Zine Brief, which will air later in 2021.
“Cancer therapies are largely not developed for children and those developed for adult cancers impact children very differently, especially with respect to both short- and long-term toxicity. New approaches are long overdue and urgently needed. Yet, by developing cancer therapy optimized for children, adults will surely benefit too, as they did at the dawn of cancer chemotherapy itself, where some of the first cures reported in childhood leukemia later translated to adults.”
Image: Timothy Triche, MD, Ph.D., is the Co-Director of the Center for Personalized Medicine Program at CHLA and Attending Physician, Professor of Pathology, Keck School of Medicine of the University of Southern California.The issues in pediatric oncology – a still overlooked sector?
According to Triche, pediatric tumors often result from inherited genetic ‘errors’ or sporadic acquired single cancer-causing events, rather than from a multitude of mutations associated with lifelong exposure to environmental factors like smoke, carcinogens, radiation, and other known cancer-causing exposures.
Childhood cancers, such as neuroblastoma, Wilms tumor or nephroblastoma, medulloblastomas, rhabdomyosarcomas, and retinoblastoma, are rarely seen in adult patients. Other common types of pediatric cancers such as leukemia, lymphoma, and brain tumors occur in adults as well.
“The cause [of cancer in adults] is very different,” Triche says “due to factors including a lifetime of exposure to alcohol, tobacco, radiation, asbestos…and other environmental factors… or simply as a result of genetic ‘bad luck’ like defects in genes that repair damaged DNA like BRCA1 and 2. This difference between the development of childhood cancer and cancer in adults necessitates a different approach to designing and optimizing novel treatment options for pediatric cancer.”
Over the last 50 years, Triche explains, major advances in the understanding of the biology of certain childhood cancers coupled with nationwide clinical trials sponsored by the National Cancer Institute has led to improved treatments and better overall survival, but a number of specific, more aggressive, cancers have not benefited from these advances. As a result, cancer remains the leading cause of disease-related death in children and adolescents.
Childhood cancers originate differently than adult cancers, with fewer actionable targets, where mutated genes induce dysregulated growth. This dysregulated growth and invasive cell behavior can now be targeted with agents developed in the past few decades. “We can now define specific genetic defects and identify [actionable] targets in childhood cancer, and yet, approved therapeutics have not been developed, Triche explained.
Triche argues that the development of ‘personalized’ therapies in challenging adult cancers like breast and colon cancer has advanced far more than in pediatric oncology. “The lack of targeted treatment agents in pediatric cancer means that precision or personalized medicine approach in children is not yet feasible and therefore, oncologists continue to mostly rely on standard chemotherapy often developed over 50 years ago. While chemotherapy has resulted in dramatically increased survival, the treatment often leads to both acute and long-term adverse effects, including cardiovascular events, chronic illness, and secondary malignancies, with an overall diminished health-related quality of life”.
Pointing to the relatively small number of children diagnosed with cancer, Triche says: “Childhood cancers represent approximately 1% of all new cancers diagnosed in the United States, and maybe another 2% of patients over 15 years of age, the Adolescent and Young Adult, or AYA, population who develop ‘pediatric’ cancers,” Triche added.
“That’s only 3% of the total cancer patient pool, but with so few patients suffering from a variety of rare cancers, it gets little attention. “Conducting clinical trials in children is also still much more complex”, Triche observed. “Therefore, sadly, for both economic and practical reasons we generally only see new cancer drugs for the treatment of children that have been developed for adults and adventitiously are effective in children, like the new class of NTRK inhibitors, developed for adult cancer but also very effective in selected pediatric cancers.”
Pediatric drug innovation
This is despite a number of very helpful federal initiatives to develop drugs for childhood cancers. The Federal Government has led the way with several support programs and some of these, like the recently renewed RACE act, are designed to FastTrack pediatric drug innovation and reward the companies who develop such treatments,” Triche says.
Triche added “while the ‘blockbuster model’ has served the pharmaceutical industry well for adult disease, that approach does not work in the development of effective precision medicine approaches that involve novel, often expensive, technology for small patient cohorts.” Triche believes that this ongoing focus on targeted therapies will ultimately benefit pediatric drug development as well if only because some of the “new” markets for the treatment of adult cancers target smaller adult cancer patient populations than those for some childhood cancers, thus encouraging drug development for pediatric cancers as well.
Can we target and treat better now?
Chemotherapeutic approaches have nonetheless dramatically improved the survival of children with leukemia, lymphoma, neuroblastoma, Wilms tumor, some brain tumors, retinoblastoma, and most sarcomas. However, despite this success, the development of treatment-related dose-limiting toxicities (DLT) in normal, healthy tissues, even at sub-curative therapeutic doses, limits the clinical utility and efficacy of most cytotoxic therapy.
Triche and his collaborators are trying to solve this problem.
“It’s not that chemotherapy does not work…” he explained, “But we often can’t give enough to cure the patient without unacceptable damage to essential normal tissues like bone marrow, heart, kidney, and liver in the process. So how do we give more drugs to the tumor cells and less to ‘everything else’, thereby averting DLT? We have been exploring the use of nanotechnology, where we package drugs in a nanoparticle that targets or preferentially binds to and is taken up by tumor cells, thereby delivering the drug where it is intended while limiting off-target toxicity. The basic approach has been explored and tried before in many liposomal formulations, but there have always been challenges, like finding a tumor-specific target, or stability limitations, or toxicity related to specific formulations.”
Targeted Nanospheres
However, a promising and flexible approach is being developed with Targeted Nanospheres (TNS), a proprietary nanoparticle formulation designed to obviate these issues. Triche is the Chief Medical Officer and co-founder of NanoValent Pharmaceuticals (Bozeman, Montana), a small and privately held company born out of a collaboration between Triche, Children’s Hospital Los Angeles, and a veteran lipid chemist, Jon Nagy, Ph.D. [1] They have created a range of TNS based products that incorporate existing cancer drugs as a ‘payload’ into patented, highly optimized Hybrid Polymerized Liposomal Nanoparticles (HPLN), that are targeted by monoclonal antibodies affixed to the outside of the HPLN, thus forming the TNS.[2]
“As each HPLN is able to be loaded with significant quantities of drug payload we have in effect enabled a safe and ‘super ADC’ (antibody-drug conjugate),” Triche suggests, “designed specifically for pediatric cancers, but also applicable to adult cancer as well”. How then does the TNS work? “We already have untargeted nanoparticles that show enhanced permeability and retention in the tumor, referred to as passive targeting, as we see with successful untargeted larger nanoparticles like Abraxane and Doxil. But by using antibodies bound to the outside of the nanoparticle we create a targeted nanoparticle that binds to tumor cells expressing that antigen, enabling active targeting of the TNS to specific tumors. For leukemia, CD19 antibody is effective. For Ewing sarcoma and glioblastoma multiforme, CD99 is particularly effective. For a broad variety of cancers, B7H3 appears to be a useful and widespread tumor antigen. If nanoparticles bind to tumor cells more than any normal tissue, you get enhanced drug delivery to tumors while limiting exposure of normal tissue resulting in reduced toxicity.”
Triche continues “NanoValent’s TNS achieve significantly greater drug delivery to tumor than untargeted nanoparticles or conventional liposomal nanoparticles. However, in addition to targeting, TNS therapeutics have apparently favorable pharmacokinetic properties as the patented HPLN lipid formulation stabilizes the nanoparticle while enabling prolonged biodistribution, tumor retention, and controlled drug release”.
Preclinical development
The company’s lead and proof of concept investigational compound, NV103, targets CD99, a cell surface glycoprotein involved in cell migration, T-cell adhesion, and transmembrane protein transport, expressed in selected tumors. “CD99 is overexpressed on Ewing sarcoma (ES) cells and is considered to be a reliable target for binding of our targeted nanoparticles. It is also present on glioblastoma cells and over 40 other tumors, making it an attractive target for our targeted drug development program,” Triche explains.
Scientists at Nanovalent have developed Hybrid Polymerized Liposomal Nanoparticles (HPLN), a proprietary technology, designed to provides a unique new nanoparticle encapsulating platform to harness and enable vastly superior targeting to the tumor and other specific cell surface antigens. Unlike other targeted technologies, the ‘payload’ incorporated into HPLN enables powerful targeted nanospheres (TNS) which can be more easily user selected, including proven cytotoxics, nucleic acid-based entities, or small molecules, or even any mixture thereof.NV103 uses ‘encapsulated’ irinotecan, a camptothecin analogue that has, over the last decade, also become an important therapeutic agent for the treatment of pediatric sarcomas such as ES. However, dose-limiting toxicity has limited the effective use of the drug. “Using our platform technology,” Triche explains, “we can ‘package’ irinotecan in a CD99-TNS and deliver as much as 100-fold more drug-to-tumor than normal tissue, thereby reducing or eliminating dose-limiting toxicity and increasing efficacy.” [3]
Preclinical studies confirm the safety and efficacy of NanoValent’s TNS drug-candidates. Results from xenograft murine models of human ES treated with NV103 demonstrated the agent effectively eliminated the tumor xenografts with no detectable off-target toxicity. Further, the ED50 of NV103 was 10 to 40-fold less than free irinotecan or untargeted nanoparticles. These studies are consistent with earlier findings from several in vitro studies demonstrating that NV103 was a potent anti-tumor formulation.[3]
“We have also demonstrated that “rescue” dose intensification with NV103 can overcome relative chemoresistance, something that is never seen with free irinotecan, due to DLT,” added Triche.
Customized delivery and targeting for still emerging drugs?
Triche notes that while the company’s platform technology may sound like ‘just another nanoparticle’, it is actually an advanced and innovative nanoparticle technology with unique properties, notably dramatically enhanced drug delivery to tumor cells with limited exposure of normal tissues to the drug, a property that is not seen with other, untargeted formulations. “While the technology may borrow from earlier developments, concepts, and principles, we have significantly advanced this technology by focusing on a unique combination of factors leading to a novel nanosphere technology. By doing so, we find that TNS effectively compete with or surpass existing formulations, including antibody-drug conjugates, liposomal drug formulations, and other nanoparticle technologies,” Triche concludes. And he notes, TNS technology is very flexible. “Not only can we encapsulate and deliver a variety of small molecule therapeutic agents, including other cytotoxics like doxorubicin, we can also deliver nucleic acids including silencing RNAs, anti-sense oligonucleotides, and CRISPR/Cas9 RNP therapies, and we can target them with a variety of affinity agents, from antibodies to aptamers. We also discovered that TNS effectively cross the blood-brain barrier. As a result, we are conducting a very promising pilot program in glioblastoma that could potentially lead to the treatment of neurological diseases beyond cancer.”
Reference
[1] Garcia D. NanoValent Receives Patent for Novel Targeted Polymerized Nanoparticles. August 20, 2019, Onco’Zine.
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