Nanoparticle Approach to Improve Safety and Cost of Cancer Treatment

Lung accounts for 1 in 5 cancer deaths. While immune checkpoint inhibitors and chemotherapies have improved survival in a subset of patients with lung cancer, their effectiveness is limited, with only a small number of patients responding to ICIs, and chemotherapy often inducing systemic toxicity, highlighting the need for combination therapies. Additionally, these treatments alone have not prevented the relapse of cancer, which can lead to patients needing multiple rounds to be effective, increasing costs significantly. In third-world countries, these treatment costs pose a formidable barrier. Many lack access to basic healthcare, let alone expensive cancer therapies. This economic disparity results in countless lives lost due to untreated cancer. Additionally, the risk of infection associated with chemotherapy complicates treatment in non-sterile environments prevalent in these regions, further exacerbating the disparity in access to care.

We have utilized nanoparticles to synergize Doxorubicin (DOX), a chemotherapy agent, with a PD-L1 antibody, an immunotherapeutic, aiming to enhance treatment efficacy while minimizing side effects and costs. DOX induces cancer cell death and releases cancer antigens, training the immune system to recognize and kill cancer. This synergizes with the PD-L1 inhibitor, which targets immune checkpoint pathways. Nanoparticles facilitate the co-delivery of these agents, leveraging their distinct mechanisms of action for improved therapeutic outcomes.

By harnessing the power of the immune system, our treatment aims to reduce reliance on costly medications and improve safety profiles, thus easing the burden on patients. Our immunogenic cell death (ICD) data shows a high expression level of ICD biomarkers (calreticulin), indicating the nanoparticle's potential to release antigens that will train your T-cells in your adaptive immune system. Our Cell-Titer Glo assay reveals that the immuno/chemo conjugated nanoparticle exhibits a superior reduction in cell viability compared to free DOX at equivalent concentrations, suggesting potential for reduced systemic toxicity. By enhancing treatment efficacy and mitigating side effects, we aspire to make life-saving cancer therapies accessible to all, regardless of geographical or socioeconomic constraints.

The target population consists of lung cancer patients globally, particularly those facing socioeconomic challenges and limited access to healthcare, including those in third-world countries. These individuals are underserved due to barriers such as high treatment costs, limited access to advanced therapies, and inadequate healthcare infrastructure.

Our solution aims to directly and meaningfully improve their lives by addressing these challenges. By utilizing nanoparticle technology to co-deliver chemotherapy and immunotherapy, we offer a safer, more effective treatment option that reduces reliance on costly medications and minimizes systemic toxicity. This approach enhances treatment outcomes while potentially reducing the need for multiple rounds of therapy, thus alleviating financial burdens. Additionally, by training the immune system to target cancer cells, our solution provides a novel avenue for improving long-term survival and reducing the risk of cancer relapse. Overall, our innovation seeks to democratize access to advanced cancer care, ensuring that all patients, regardless of their socioeconomic status or geographical location, can receive the treatment they need to live healthier, fuller lives.

Our team is uniquely positioned to design and deliver this solution to underserved communities due to our personal and professional connections to these regions. The company we partnered with is a Thai company, and Thailand is still developing in terms of healthcare access and infrastructure. This partnership allows us to directly engage with communities in Thailand and understand their specific needs and challenges related to cancer care.

Furthermore, I, as the team lead, come from South Africa, a severely underdeveloped country where access to healthcare is limited, particularly for complex and costly treatments like cancer therapy. Tragically, I recently experienced the loss of a close family member in South Africa due to cancer, in large part due to the need for multiple costly rounds that took a large toll on their body and their bank, highlighting the urgent need for improved access to affordable and safe treatments.

Our team's diverse backgrounds and personal experiences inform our approach to designing and implementing the solution. We are deeply committed to ensuring that the voices and perspectives of the communities we serve, including those in Thailand and South Africa, are central to our decision-making process. Through ongoing dialogue, collaboration, and partnerships with local stakeholders, we strive to incorporate community input, ideas, and agendas into every aspect of our solution, ensuring that it is tailored to address the specific needs and challenges faced by these underserved populations.

As of now, we have developed and tested a prototype of our nanoparticle-based co-delivery system for chemotherapy and immunotherapy. Initial in vitro experiments have shown promising results in terms of efficacy and safety profiles. Our team has conducted rigorous testing to optimize the formulation and delivery mechanism, ensuring maximum effectiveness and minimal side effects.

While our solution is still in the early stages of development, we have successfully engaged with the Knight Cancer Research Advocates group to gather feedback and refine our approach. 

We are looking to gain access to critical funding resources to further our research in vivo, connections with experts and mentors who can provide feedback, and networking opportunities with the research community. 

Instead of solely focusing on pouring millions into funding new research, our approach innovatively combines existing treatments to create a synergistic solution. By leveraging the collective knowledge and advancements in chemotherapy and immunotherapy, we maximize the potential of these existing therapies through our nanoparticle co-delivery system. This integrated approach not only streamlines the development process but also ensures that our solution is grounded in established scientific principles and clinical evidence.

As for broader applications, while initially developed for lung cancer, our innovative approach has the potential to benefit patients with various types of cancer, since Doxirubicin and PD-L1 inhibitors are improved in a variety of cancer types. Furthermore, the use of nanoparticles can inspire further research in fields beyond cancer. This could lead to groundbreaking advancements in areas such as infectious diseases, autoimmune disorders, and neurological conditions, ultimately improving outcomes for patients across diverse medical specialties.

Combination therapies have demonstrated significant efficacy in the past, with numerous studies showcasing their ability to improve treatment outcomes compared to single-agent approaches. By combining multiple treatment modalities, such as chemotherapy and immunotherapy, these approaches capitalize on synergistic effects, targeting cancer cells through multiple mechanisms of action simultaneously. This strategy has led to enhanced tumor regression, prolonged survival, and improved quality of life for cancer patients.

Building on this foundation, we expect our nanoparticle-based co-delivery system to have a similarly profound effect when tested in vivo. In preclinical studies, we have already observed promising results, and as we move forward with in vivo testing, we expect to further validate these findings and demonstrate the efficacy and safety of our combination therapy approach.

Impact Goal: Our impact goal is to significantly improve cancer treatment outcomes and accessibility for underserved populations globally, particularly in low- and middle-income countries.

Measuring Progress:

1. Treatment Efficacy: We will measure the response rates, tumor regression, and overall survival rates of patients receiving our nanoparticle-based co-delivery system compared to standard treatments.
2. Reduction in Side Effects: We will track the incidence and severity of treatment-related side effects, such as nausea, fatigue, and immune suppression, to assess the impact of our solution on improving patients' quality of life.
3. Affordability and Accessibility: We will monitor the cost-effectiveness of our treatment and assess its affordability for patients in different socioeconomic contexts. Additionally, we will track the expansion of access to our solution in low- and middle-income countries, including the number of patients reached and treated.
4. Long-Term Survival and Cancer Recurrence: We will evaluate the long-term survival outcomes and rates of cancer recurrence among patients receiving our treatment to assess its effectiveness in preventing disease progression and improving long-term prognosis.

In our solution, we used a variety of nanotechnology approaches to test our innovation in preclinical studies. 

We started by loading the drugs on our nanoparticle: 

MSNP silica core was coated with polyethyleneimine (a reagent that allows for the binding of drugs) and polyethyleneglycol (a stabilizing agent to prevent aggregation), creating PDX-NP. PD-L1 antibody (avelumab) was then conjugated on PDX-NP (A-NP). For drug loading, DOX was mixed with A-NP in phosphate-buffered saline (PBS) for overnight shaking (350 rpm) at room temp. DOX loading was quantified by centrifugation, the supernatant was removed, and absorbance was measured (496 nm). Size and charge of A-DOX-NP was measured using Zeta Sizer (Malvern, ZS-90). 

We then did a PD-L1 antibody test to evaluate the efficacy of the immune checkpoint inhibitor: 

Cell lines were treated with A-NP and NP, followed by flow cytometric analysis to evaluate PD-L1 expression through fluorescent antibody staining. PD-L1 expression quantified for data analysis.

Furthermore, we did a Cell-Titer Glo assay to test cell viability after treating with A-DOX-NP:

In vitro cultured cell lines were treated with A-DOX-NP, A-NP, free DOX, or PBS. Cellular viability was assessed three days post-treatment using the Cell Titer-Glo Luminescent Cell Viability Assay, measuring ATP levels. 

Finally, our most prominent data was our Immunogenic Cell Death data:

Cell lines were treated with A-NP, free DOX, and A-DOX-NP. Flow cytometric analysis was then performed to measure calreticulin staining, indicating ICD. The flow cytometry data was analyzed to quantify the expression levels of calreticulin markers related to ICD receptors.

I am the team leader for this project, however, I worked in collaboration with PDX Pharmaceuticals, a company that operates out of the Yantasee laboratory at Oregon Health and Science University. I worked with the CEO of the company to discuss my proposal, and then with three grad students to execute it. 

One year for my project in particular, but the company has been testing different nanoparticle constructs for the last 14 years.

Our team is committed to fostering diversity, equity, and inclusion within our organization and in the broader community that we serve. Our team is comprised of individuals from diverse backgrounds, including different cultural, ethnic, and socioeconomic identities. One big way that we meet our goals is through engaging with diverse communities in order to understand their unique needs and perspectives. 

As our innovation is undergoing preclinical trials, we are not yet serving the community. However, our business model will involve distributing our nanoparticle delivery system to healthcare providers who will then be able to offer their patients our unique innovation. We will provide these products and services through a combination of direct sales, partnerships with healthcare institutions, and collaborations with government agencies and non-profit organizations. Our revenue model will be based on a combination of product sales, licensing agreements, and service fees. Additionally, we may explore opportunities for grant funding, investment, and philanthropic support to further advance our mission of making innovative cancer treatments accessible to all.

Currently, our company's preclinical studies are funded through support from NIH (NCI, NCATS, NIDDK, NIGMS, NIEHS, NIAID), ONAMI, OHSU, PNNL, and Foundations (Prospect Creek, Wayne D. Kuni & Joan E. Kuni, Gordon Moore, Hillcrest, Women’s Health Circle of Giving). PDX Pharma has raised about $13.5 million of financing to date, and money from this fund was used to perform these studies.