Why Not Kids?

Improving Access and Outcomes for Pediatric Oncology Patients in Kentucky:
A Proposal from the KY Pediatric Cancer Research Trust Fund

Cancer is the leading cause of death by disease in childhood. Yet cancer is also the most potentially curable chronic illness in childhood, and recent advances have dramatically improved the outcome for some of the more common pediatric cancers. For example, cure rates for the most common pediatric cancer, acute lymphoblastic leukemia, have gone from < 10% to well over 80% in the past fifty years. These remarkable gains have come about through a commitment to thoroughly understand the disease process, to develop collaborative and innovative clinical trials, and to improve access for patients to be treated in centers specializing in these diseases. Investing in childhood cancer care can lead to a tremendous long-term benefit for society in terms of life-years that are saved by successful treatment, especially considering that the average age at diagnosis is 6 years for children with cancer compared to 66 years for adults.

We propose that the best way to improve childhood cancer care in Kentucky is to partner with the state’s two pediatric oncology centers to simultaneously address several initiatives that focus on understanding disease, developing clinical trials, and improving access. Pediatric oncologists and researchers at the University of Louisville and the University of Kentucky will work on these initiatives in an effort to improve pediatric cancer care both at their institution as well as collaboratively for patients across the state. Each center has inherent strengths, as well as areas that should be expanded. This proposal capitalizes on both, and offers the potential for working together to make sure patients throughout the entire state can benefit from this investment. The key areas of focus include:

• Improving access to care for adolescents and young adults diagnosed with pediatric-type cancers
• Combining epidemiologic and genetic research to help better understand the higher incidence of certain types of pediatric brain tumors seen in specific counties in central and eastern Kentucky
• Recruitment of disease-specific pediatric cancer researchers whose mission will be the translation of research findings into the development of innovative and collaborative clinical trials, with a particular focus on combining molecularly targeted therapies with existing conventional treatments
• Exploring the radiomic assessment of imaging studies in pediatric sarcoma patients in an effort to find features that can impact clinical decision making
• Expansion of efforts to further basic science and clinical research in cellular therapy and other immune-based treatment strategies

Each of these projects is described in more detail below. General budgets and broad cost estimates are provided and include funding to be distributed over a 2-year period. The KY Pediatric Cancer Research Trust Fund board, a broad-based steering committee, with participation of medical care providers, public health experts, clinical outreach professionals, and community representatives from across Kentucky will coordinate, supervise, and monitor these projects while fostering a spirit of collaboration and shared resources and information. Because specific costs of projects are often hard to predict, the steering committee will be able to re-allocate funds between these projects so a more appropriate distribution of support is provided once final costs are known.

Synopsis: Recent advances in biomedical research have generated several emerging technologies that show promise in leading to the development of novel anti-cancer therapies in the near future. One example is the use of CRISPR-Cas9-based genome editing technology to generate “designer” immune cells, which, by abrogating an immune checkpoint mechanism that allows cancer cells to evade elimination, will make the immune cells more effective in killing cancer cells. Another example is the development of virus-specific killer T cells through targeted immunologic stimulation, which could be used to treat life-threatening viral infections often seen in cancer patients. We propose a focused effort to embrace these emerging technologies and develop novel anti-cancer treatments in molecularly targeted therapy, immunotherapy and cellular therapy. The study of these up-and-coming therapies may not directly benefit the current generation of children with cancer but will lay a critical foundation for the development of innovative therapies for children of tomorrow. Importantly, this effort could help establish Kentucky as a major center for medical innovation and provision of outstanding pediatric cancer care.

Areas for which support is requested include the funding of a Cancer Therapy Specialist, who will develop next-generation chimeric antigen receptor (CAR) T cells that can effectively target acute myeloid leukemia, brain tumors and sarcoma, a Cellular Immunology Specialist, who will establish techniques to produce virus-specific killer T cells that can eliminate serious viral infections associated with cancer, and a Laboratory Technologist, who will optimize the application of these new technologies to preclinical and clinical testing. The funding requested will also provide necessary laboratory support for characterization of these new therapeutic products and validation of their effectiveness in animal models before moving on to early-phase clinical trials.

The cost estimate for this project is $2 million, which will be disbursed over a two-year period.

Desired outcome: This project is expected to result in the development of new therapeutics products that can effectively fight several forms of pediatric cancers, such as brain tumors and sarcoma, which are often resistant to conventional therapies. These efforts will help put Kentucky on the map as a major center for medical innovation and compassionate pediatric cancer care.

Synopsis: The past decade has seen the exciting introduction of many new and effective therapies that directly benefit pediatric patients with cancer. Examples include chimeric antigen receptor (CAR) T cell therapy, which is very effective in the treatment of refractory B-cell acute lymphoid leukemia, and haplo-identical stem cell transplantation with TCR-alpha-beta T cell depletion, which minimizes the risk of post-transplant graft-versus-host disease in leukemia patients who do not have conventional donors. Many of these new therapies, however, are only available to patients in the context of formal clinical trials, and patients being treated in clinical programs not participating in these trials would be deprived of the opportunity to receive these therapies. To ensure that promising new therapies will be available to children with cancer in Kentucky, we propose to strengthen the clinical research infrastructure in our programs and actively participate in new clinical trials that offer innovative therapies. We envision that, by enlisting the support of dedicated clinical research professionals, the clinical teams will be able to participate in multi-institutional clinical trials that offer promising new therapies. In turn, increased participation in large-scale trials to evaluate clinical effectiveness of novel therapies will allow the clinical teams to enhance their contribution to productive research in pediatric cancer care.

Areas for which support is requested include the funding of two Clinical Research Associates, who will assist in opening of new clinical protocols and supervise patient enrollment, sample collection, and data aggregation, and a Research Data Analyst, who will assist in clinical data entry, management, analytics, and reporting.

The cost estimate for this project is $1 million, which will be disbursed over a two-year period.

Desired outcome: It is expected that the two clinical teams, with the support from dedicated clinical research professionals, will establish robust clinical research programs that complement each other and bring in new clinical trials and innovative therapies that will benefit children with cancer in Kentucky. 

Synopsis: Adolescent and young adult (AYA) patients up to the age of 30 years may develop cancers that are commonly cared for by pediatric oncologists, such as leukemia, sarcoma, and lymphoma. In many rural locations, patients over 15 years of age are often cared for in their local community by adult oncologists who more commonly treat malignancies in older patients (e.g., breast, lung, and prostate cancer), and who may not be familiar with optimum therapies for this younger patient population. Data suggests that for AYA patients who develop these cancers, outcomes are best when care is delivered in a center which has expertise in managing the medical and social issues seen with this patient population. In addition, the fragmentation of care over a variety of non-specialized centers has led to very low clinical trial enrollment, which likely explains the lack of improved survival for this population over the past few decades. Therefore, this group of patients represents an underserved population with a historically poor outcome. We believe outcomes will be improved most rapidly if distinct AYA centers are developed within the state to more adequately and comprehensively address the specific needs of this patient population. The University of Louisville has recently opened a dedicated AYA center in conjunction with the Norton Cancer Center, and the University of Kentucky has obtained administrative support for the development of such a program to be associated with the Markey Cancer Center. These programs need to be directed and staffed by pediatric oncologists, as the treatment strategies and care models are based on principals widely used in pediatric oncology, and care of these patients is currently in the existing scope of practice for pediatric oncologists. The existence of two AYA centers within Kentucky is crucial due to the geographical realities of the state, as patients in the eastern portion of the state may be > 3 hours away from Louisville, making patient participation much less likely. Physician staffing and physical considerations (e.g., clinic space and supplies) for these AYA centers will be provided by the institutions.

Areas for which support is requested include the hiring of a nurse practitioner and social worker to address the unique needs of this patient population. Two key advantages of having an AYA center are not only the physician expertise, but also the access to clinical trials specifically for this population, as well as comprehensive care which can address the unique needs of this group. Nurse practitioner support specifically for this population will not only be able to assist with the medical care for these patients, but also help with education and enrollment on clinical trials. From a social support standpoint, AYA patients have historically had considerable difficulties with insurance issues, and when coupled with the psychological stress of cancer diagnosis and treatment these problems can lead to treatment abandonment and poor outcomes. Trying to maximize the supportive care for this high-risk patient population with dedicated social workers may be quite helpful for optimization of treatment and allowing these patients to complete all of planned therapy. Other requested staff include an Education and Outreach Specialist who can communicate with referring physicians and help identify and recruit potential patients who could benefit from a fully developed AYA program.

The cost estimate for this project is $1 million, which will provide two years of support for sufficient nurse practitioners, social workers, and education/outreach specialists as described above. As with all of the proposed projects, staffing will be disbursed between the two pediatric oncology centers based on needs and patient volumes.

Desired outcome: We anticipate that the full development of two dedicated AYA centers within the state will result in at least 30% more patients with pediatric-type cancers in this age group receiving comprehensive care appropriate for their age and disease. It is also expected this increase in patients seen will translate to better overall care and more clinical trial enrollments, which we predict will drive improved outcomes for this patient population.

Synopsis: Brain tumors are now the leading cause of pediatric cancer death, and so are an area in urgent need of further investigation. Epidemiologic data from the Kentucky Cancer Registry has confirmed that the most common pediatric brain tumor, astrocytoma, is seen more frequently in Kentucky than the rest of the country. This increase is particularly seen in the central and eastern portion of the state, where the incidence is even greater when comparing to the rest of the state. Spatiotemporal assessments have identified a zone of 40 contiguous counties in which the incidence of pediatric brain tumors is far higher than what would be expected by chance. Because changes in chromosomes and genes affect the development of tumors, it is logical to examine the genetic makeup of tumors that occur more frequently than expected in an effort to discover why these tumors are developing. Together with colleagues at the Children’s Brain Tumor Tissue Consortium, we will perform genetic analysis on archival tumor samples from patients who were diagnosed within these counties of interest, as well as a separate control group of children who were diagnosed in other Kentucky counties. In addition, the use of this large Tissue Consortium will help allow comparison with data from other patients across the country, increasing the relevance of our findings. Data will be reviewed by informaticians, epidemiologists, biostatisticians, molecular biologists, and pediatric oncologists in an effort to discover more about this potentially important clue in the development of pediatric brain tumors.

Areas for which support is requested include the identification, recovery, preparation, sending and returning of archival tumor samples performed by the Kentucky Cancer Registry team. In addition, funding is sought for the molecular testing and interpretation of this data.

The cost estimate for this project is $400,000, which will provide sufficient funds for the collection of samples through the Kentucky Cancer Registry, and the extensive genetic testing of these tissue specimens through the Children’s Brain Tumor Tissue Consortium, and the analysis of this data by pediatric oncologists and other specialists at the University of Kentucky.

Desired outcome: This project will allow for a comprehensive assessment of a Kentucky-specific problem that could impact our understanding of how pediatric brain tumors develop, including the identification of possible risk factors or therapeutic targets.

Synopsis: The use of therapies specifically tailored to the genetic make-up of an individual patient’s cancer cells is termed targeted therapy, and this strategy has revolutionized the field of cancer research. These treatments offer the hope of more effective and less toxic therapy, and several targeted therapies have now received FDA approval for treatment of adult malignancies. There are multiple ongoing trials of targeted therapies in pediatric oncology as well, although therapeutic targets are less frequent and less easily exploited. It is likely that optimal use of targeted therapies may require integration with existing conventional treatments such as radiation or standard chemotherapy. This would represent the next generation of clinical trials, and it is important to be on the forefront of this upcoming wave of research. Recruitment of a top-level researcher not only increases the prestige of an institution, but also improves the overall scientific environment and can lead to advances in a wide variety of areas.

Areas for which support is requested include the recruitment of a basic/translational scientist at each institution who would lead efforts for the development of novel treatment strategies involving targeted therapies and their integration with conventional treatment. Areas in greatest need include brain tumor and sarcoma, as these two diseases account collectively for nearly 40% of pediatric cancer deaths. Both universities have strong clinical programs in these areas, including pediatric neurosurgeons, orthopedic oncologists, and radiation specialists who are qualified to provide excellent care for these patients, providing an excellent clinical complement for researchers in these areas.

The cost estimate for this project is $ 2 million, which would allow for recruitment of two basic/translational scientists and cover necessary laboratory start-up costs. Both the University of Louisville and the University of Kentucky would each be assigned one researcher, with the intention that any clinical trials resulting from their work would be performed at both institutions.

Desired outcome: It is expected that data from the laboratories of these basic/translational scientists will result in the initiation of clinical trials for pediatric patients with sarcoma or brain tumors.

Synopsis: Radiomics is the high-throughput extraction of quantitative information from routine imaging studies which allows for further characterization of tumors. Using computerized algorithms, radiomic evaluation can quantify various features of tumors seen on CT or MRI scans, and this information can be used in a variety of ways. For example, radiomic evaluation has been shown to help differentiate malignant from benign masses, to identify which sarcomas are more likely to metastasize, to predict which molecular alterations may be present in a given tumor, and to help identify which patients may be most responsive to certain therapies. Importantly, all of this information can be gleaned from routine scans that are done as part of regular clinical care, and the analysis can be done retrospectively. While multiple applications for radiomic evaluation of adult malignancies have been reported, data with pediatrics is sparse so far. The University of Kentucky has recently presented information showing that radiomics can help identify which small lung nodules may be malignant vs benign in pediatric sarcoma patients. If the preliminary results are validated in a larger cohort of patients, this information would be very useful in guiding clinical decision making, as patients with small indeterminate lung nodules often undergo additional scans or surgeries to clarify the true nature of the nodule. This is another growing field in oncology, and we are looking to position Kentucky at the forefront of this area of investigation. In addition, this project represents a great opportunity for collaboration between the two institutions, as scans from both institutions could be retrospectively reviewed at one central site.

Areas for which support is requested include the funding of a postdoctoral student to help lead the investigation of imaging studies of pediatric sarcoma patients using technology currently in place at the University of Kentucky. In addition, additional resources for biostatistical support and presentation of research results are requested.

The cost estimate for this project is $400,000, which will be disbursed over a two-year period.

Desired outcome: It is expected data from preliminary experiments will be validated in a larger group of patients, and important information can be discovered about how radiomics can be applied to the clinical management of pediatric sarcoma patients.

Synopsis: The pediatric cancer care teams at University of Louisville and University of Kentucky both have outstanding clinicians and supporting staff and are currently providing high-quality care to their patients. Nevertheless, there are many areas of clinical service that can be further enhanced. These areas will need to be systemically identified and the possible routes of improvement reviewed, discussed and implemented. These efforts will be best supported by the availability of a dedicated quality improvement professional, whose expertise can be tapped to identify potential weaknesses in the current cancer care practice and propose plans for enhancement. Likewise, the support of a dedicated data analytics professional will facilitate collection of critical data that can be used to perform evidence-based analysis of the effectiveness of the cancer care service, whereas the availability of an education and community outreach professional will be able to bridge gaps that might exist between the current cancer care practice and the true needs of the community. Working closely with the medical teams, these professionals could shed light on areas of inadequacy that have been overlooked and bring pediatric cancer care in Kentucky to a higher level of excellence.

Areas for which support is requested include the funding of a Quality Improvement Specialist, who will spearhead comprehensive efforts to enhance the quality of clinical services provided to patients at the two institutions, a Clinical Data Analytics Specialist, who will collect data on treatment effectiveness, analyze clinical outcome measures and identify areas of weakness that can be targeted for improvement, and an Education and Community Outreach Specialist, who will design educational activities for both medical care providers and patients and organize outreach programs to enhance public communication.

The cost estimate for this project is $1 million, which will be disbursed over a two-year period.

Desired outcome: It is expected that the pediatric cancer care teams, with assistance from the quality improvement, data analytics and outreach professionals, will be able to establish a concerted effort to reach the highest level of clinical excellence and provide the best possible care for pediatric cancer patients in Kentucky.

Synopsis: The development of new therapies to fight childhood cancer requires essential laboratory infrastructure that allows the production, validation and safety assurance of therapeutic products. Novel therapeutic products to be used in clinical trials will need to undergo extensive preclinical characterization and efficacy testing before they can be used in patients. The CliniMACS cell processing system, for instance, is commonly used to produce therapeutic cellular products, as the system ensures sterility and integrity of the products. A bioluminescence-based live animal imaging system, such as the IVIS Spectrum system, is the standard approach used to demonstrate the ability of anti-cancer immune cells to shrink human tumors, whereas fluorescence-activated flow cytometers and cell sorters are standard laboratory tools used to demonstrate the purity and identity of cell therapy products. To ensure that we will have the ability to develop novel therapies that can be moved quickly to clinic al application, we propose to establish the laboratory infrastructure necessary for rigorous production, validation and testing of therapeutic products.

Areas for which support is requested include the acquisition of a CliniMACS Prodigy cell processing system, which will be used for large-scale manufacturing of therapeutic cell products for clinical application, an IVIS Spectrum in vivo imaging system, which will be used to evaluate the ability of cellular therapy products to eliminate cancer cells in live animals, and a multi-parameter flow cytometer and cell sorter, which will be used to analyze and prepare immune cells required for developing effective immunotherapy of cancer. The funding requested will also support the purchase of laboratory supplies necessary for the operation of these systems.

The cost estimate for this project is $2 million, which will be disbursed over a two-year period.

Desired outcome: The availability of these essential biomedical research tools will vastly enhance the ability of the translational and clinical research teams to develop innovative and effective therapies to fight pediatric cancer in Kentucky.