Immunotherapy can work wonders for patients with cancer, offering renewed hope and second chances. However, its effectiveness is limited, with only 20-40% of patients responding to these treatments. Faced with this challenge, cancer researchers have been scurrying for ways to improve success rates. Over the past decade, we've learned that immunotherapy only works in "hot" tumors—those infiltrated with T cells ready to engage. Yet, cancer cells often outsmart the immune system, evading detection, feigning innocuity. Checkpoint inhibitors, a recently deployed therapeutic class, act to remove the metaphorical brakes on the immune system, enabling it to attack cancer cells. However, this strategic suppression of T cells by the tumor repels them, rendering immunotherapy powerless, and leaving the tumor in a "cold" state. Without T cells acting as soldiers, the immune system lacks the tools to fight the war. Researchers are now in a race against time, striving to defrost the immune system, activate it, and melt away tumors.
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Reigniting the immune system in melanoma
Enter John Harris, MD, PhD, and his colleagues, pioneers in the quest to reignite the "cold" immune system in melanoma—a skin cancer diagnosed in its invasive form in approximately 100,000 people annually in the United States. Previous research by this team showed that melanoma-derived DNA triggers immune reactions within dendritic cells (a type of immune cell) by activating the absent in melanoma 2 (AIM2) pathway. Dendritic cells also harbor another immune pathway—stimulator of the interferon gene (STING). In melanoma, the AIM2 pathway mysteriously suppresses the STING pathway, fostering tumor progression.
“We hypothesized that by silencing the AIM2 gene, we could disinhibit the STING pathway and transform the ‘cold’ tumor into a ‘hot’ one,” explains Dr. Harris. In an earlier study, they demonstrated that silencing AIM2 unleashed the STING pathway, facilitating T cells' infiltration into the tumor. Their short interfering RNA (siRNA) drug not only initiated an anti-tumor response in mice and human dendritic cells in vitro but also inhibited the recruitment of regulatory T cells (T regs) as a bonus. “T regs are good in autoimmunity [situations] because they turn off the [unwanted] autoimmune response, but they're detrimental in tumors because they turn off the anti-tumor immune response,” notes Dr. Harris. Their results indicated success when the drug was used either alone or in conjunction with immunotherapy.
Despite these promising results, investors lacked interest because the drug worked as a cellular therapy. The production of cellular therapies is cumbersome, involving the extraction of cells from frail patients. In this case, these cells must be converted into dendritic cells, pretreated with the siRNA drug, and finally reintroduced to the patients. Recognizing these complexities, investigators indicated that if the team could develop a siRNA capable of 'self-delivering' into tumor dendritic cells, their interest would be piqued.
Challenge accepted: A journey to self-delivery
With this refined mission, the team secured a Cancer Center grant to devise a way for the siRNA to self-deliver. Under the skilled guidance of Anastasia Khvorova, PhD, the team chemically modified the siRNA, ensuring it could successfully reach the tumor and wiggle its way inside. Next, they were awarded funds from the BRIDGE Innovation and Business Development Office, to propel their siRNA drug toward clinical trials.
The pot of gold is now within their reach. “Our current goal is to optimize the siRNA, enhancing efficacy, efficiency and durability. We also seek to track the drug's path—does it reach the dendritic cells in the tumor or is there another parallel pathway at play?” asks Dr. Harris.
The final step involves testing the drug in non-human primates, ensuring it takes effect in at least 50% of tumor cells. Non-human primate testing is crucial, offering insights into the drug's behavior in a living system closely related to humans.
“This milestone ensures safety and appropriate biodistribution. If the drug behaves as intended without causing harm to the animals, we can confidently proceed to the next step,” states Dr. Harris.
A potential breakthrough: Awakening the immune system
The team is diligently piecing together the puzzle, potentially offering a way to awaken the immune system in melanoma. With a self-delivery mechanism, this groundbreaking therapeutic approach not only holds great potential for melanoma but also presents a promising avenue for broader applications across a spectrum of cancers and complex diseases.
