Beating cancer cells at their own game by stepping on their cGAS – Wyss Institute at Harvard

Report on a Novel mRNA Immunotherapy for Cancer Treatment in Alignment with Sustainable Development Goals

Introduction: Advancing SDG 3 – Good Health and Well-being

In pursuit of Sustainable Development Goal 3 (SDG 3), which aims to ensure healthy lives and promote well-being for all, a new study presents a promising mRNA-based immunotherapy. This therapeutic approach addresses the critical challenge of cancer, a leading non-communicable disease targeted under SDG 3.4. The research focuses on reprogramming the tumor microenvironment (TME) to overcome the immune evasion strategies employed by cancer cells, thereby enhancing the body’s natural defenses against tumors.

Technological Innovation and Scientific Research: Contribution to SDG 9

This research exemplifies the principles of SDG 9, which encourages building resilient infrastructure, promoting inclusive and sustainable industrialization, and fostering innovation. The development of this therapy represents a significant advancement in scientific research and technological capability (Target 9.5).

Therapeutic Mechanism

The core of this innovation is an mRNA therapy delivered via lipid nanoparticles (LNPs) that forces cancer cells to reactivate a dormant immune pathway.

• Problem: Cancer cells often suppress the cGAS enzyme, which prevents the production of the cGAMP signaling molecule. This molecule is crucial for initiating an innate immune response against the tumor.
• Solution: The new therapy uses LNPs to deliver mRNA encoding the cGAS enzyme directly into cancer cells, along with a piece of double-stranded DNA (dsDNA) to activate it.
• Outcome: Targeted cancer cells are coerced into producing and releasing cGAMP, which in turn activates the STING pathway in surrounding immune cells, triggering a robust anti-tumor response.

Experimental Findings and Efficacy Analysis

In Vitro and In Vivo Results

The study provides substantial evidence of the therapy’s effectiveness, contributing directly to the goal of reducing premature mortality from non-communicable diseases (SDG 3.4).

1. Immune Activation: In laboratory settings, melanoma cells treated with the cGAS LNPs produced significant amounts of cGAMP, leading to a potent activation of the STING response in immune cells.
2. Tumor Growth Reduction: When tested in mouse models with melanoma, direct intratumoral injections of the cGAS LNPs reduced tumor growth.
3. Broad Immune Response: The therapy activated a wide range of immune cells, including cytotoxic CD8+ T cells, natural killer cells, macrophages, and dendritic cells, indicating the engagement of both the innate and adaptive immune systems. This broad engagement is a promising indicator of lasting anti-tumor immunity.

Synergistic Effects with Combination Therapy

To maximize therapeutic impact, the cGAS LNP therapy was combined with existing immunotherapies, demonstrating a path toward more effective cancer treatment protocols.

• The cGAS LNP therapy was administered alongside an anti-PD-1 checkpoint inhibitor, a standard form of immunotherapy.
• This combination therapy resulted in significantly improved outcomes compared to either treatment alone.
• In 30% of the mice receiving the combined treatment, melanoma tumors were completely eradicated, a result not seen with the individual therapies.

Implications for Global Health and Future Directions

Alignment with Global Partnerships (SDG 17)

The development of this therapy underscores the importance of collaboration and partnership (SDG 17) among research institutions, including the Wyss Institute, Brigham and Women’s Hospital, and Harvard Medical School. Such partnerships are vital for translating scientific breakthroughs into accessible health solutions.

Future Research and Development

The research team has outlined clear next steps to advance this technology towards clinical application.

1. Systemic Delivery: Adapt the LNP delivery system for systemic injection, allowing for treatment of metastatic cancers and improving patient accessibility.
2. Combination Strategies: Investigate synergies with chemotherapy and radiation, which damage cancer cell DNA and could potentially enhance the activation of the newly synthesized cGAS enzyme.
3. Broader Applications: The underlying principle of using mRNA to modulate immune responses has potential applications for other diseases, reflecting a platform approach to tackling global health challenges.

Analysis of Sustainable Development Goals in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

SDG 3: Good Health and Well-being

• The article’s central theme is the development of a novel mRNA therapy to treat cancer, specifically melanoma. This directly contributes to ensuring healthy lives and promoting well-being by advancing medical science to combat a major non-communicable disease.

SDG 9: Industry, Innovation, and Infrastructure

• The research detailed in the article represents a significant scientific and technological innovation. It describes the creation of a new therapeutic approach using “lipid nanoparticles (LNPs) that they loaded with mRNA encoding cGAS,” which is a cutting-edge development in the field of structural nanomedicine and immunotherapy. This aligns with the goal of fostering innovation and enhancing scientific research.

SDG 17: Partnerships for the Goals

• The article highlights collaboration among multiple prestigious institutions, including the Wyss Institute, Brigham and Women’s Hospital, MIT, and Harvard Medical School. It also mentions the establishment of the “Targeted Nucleic Acid Delivery Working Group at the Wyss Institute that serves as a forum to facilitate internal and industry collaborations,” which exemplifies the multi-stakeholder partnerships needed to achieve sustainable development goals.

2. What specific targets under those SDGs can be identified based on the article’s content?

SDG 3: Good Health and Well-being

1. Target 3.4: By 2030, reduce by one-third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
   • The research aims to create a more effective treatment for melanoma, a non-communicable disease. The article states that the combined therapy “further improved the therapeutic outcomes. In 30% of the mice, melanoma tumors were completely eradicated.” This work directly contributes to improving treatment options and potentially reducing mortality from cancer.
2. Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases.
   • The entire article is dedicated to the research and development of a “new mRNA therapy” for cancer. This work is a clear example of supporting R&D to find new medicines for major non-communicable diseases.

SDG 9: Industry, Innovation, and Infrastructure

1. Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries… including… encouraging innovation and substantially increasing the number of research and development workers.
   • The study showcases advanced scientific research and innovation in immunotherapy and drug delivery. The development of “cGAS LNPs” is a technological advancement that enhances the capabilities of the biomedical sector. The publication of the findings in “PNAS” contributes to the global body of scientific knowledge.

SDG 17: Partnerships for the Goals

1. Target 17.16: Enhance the Global Partnership for Sustainable Development, complemented by multi-stakeholder partnerships that mobilize and share knowledge, expertise, technology and financial resources.
   • The project is a result of a collaboration between researchers at the Wyss Institute, Brigham and Women’s Hospital, and Harvard Medical School. The article also mentions the “Targeted Nucleic Acid Delivery Working Group” designed to “facilitate internal and industry collaborations,” demonstrating a partnership model for sharing knowledge and technology.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

SDG 3: Good Health and Well-being

• Implied Indicator for Target 3.4: The article provides data on treatment efficacy in a preclinical model, which serves as a proxy for progress towards reducing mortality. The specific measure mentioned is the rate of tumor eradication and reduction in tumor growth: “In 30% of the mice, melanoma tumors were completely eradicated, while tumor growth was significantly slowed or halted.”
• Implied Indicator for Target 3.b: The development of the “new mRNA therapy” itself is an indicator of progress in R&D. The successful creation and testing of this novel therapeutic approach can be measured as a key R&D outcome.

SDG 9: Industry, Innovation, and Infrastructure

• Implied Indicator for Target 9.5: The publication of the research in a high-impact scientific journal, “a new study published in PNAS,” is a direct indicator of research and development output. The technological innovation itself, the “cGAS LNP therapy,” is another measurable outcome of this enhanced scientific research.

SDG 17: Partnerships for the Goals

• Implied Indicator for Target 17.16: The existence of collaborative bodies and projects is an indicator of partnership. The article explicitly mentions the “Targeted Nucleic Acid Delivery Working Group at the Wyss Institute” and the multi-institutional team of authors as evidence of such partnerships.

4. Create a table with three columns titled ‘SDGs, Targets and Indicators” to present the findings from analyzing the article.

Source: wyss.harvard.edu