Understanding the Journey of Cancer and Malaria Vaccine Development from Harvard Innovations

For Ed Doherty and his team, the journey to developing a vaccine against cancer and malaria has required perseverance and innovation. Doherty, a co-founder of Attivare Therapeutics, humorously remarked, “It’s going to kill me, but it’s the best thing I’ve ever done,” reflecting the dedication and complexity involved in their efforts.

At the heart of Attivare’s technology lies the creation of tiny “factories” in the body. These miniaturized structures enable immune cells to recognize and eliminate tumor cells. This method has already shown promising results during cancer clinical trials, and additional applications include a COVID vaccine developed while the team navigated the pandemic's challenges. Recently, the company secured a $6.6 million grant extension from the Gates Foundation to advance its malaria vaccine, which targets one of the world’s most severe infectious diseases.

Collaboration: The Key to Vaccine Advancement

The narrative of the vaccine initiative exemplifies the strength of collaboration among various scientific disciplines, ranging from basic research to clinical applications. This collaborative dynamic acknowledges that the path from laboratory discovery to patient rollout is rarely linear.

The story of WDVAX—initially the name for the cancer vaccine—doesn't follow a straightforward journey from lab to clinic. In fact, the project oscillated between bench and clinical settings, requiring improvements that ultimately led Doherty to leave the Wyss Institute and establish Attivare, which is now aiming to bridge the vaccine to patient administration.

The Science Behind the Vaccine

Doherty's journey is supported by a team of experts. The “factories” utilized in Attivare’s vaccines are constructed from a porous biomaterial, developed in the lab of David Mooney, a distinguished professor in bioengineering at the John A. Paulson School of Engineering and Applied Sciences at Harvard. This porous material serves as a platform for vaccine delivery, demonstrating how interdisciplinary research can yield actual medical innovations.

“There’s a two-way street here,” said F. Stephen Hodi, a professor of medicine at Harvard Medical School and director of clinical trials for the WDVAX initiative. His perspective highlights the importance of synergy among various research teams, a factor that can accelerate discovering and implementing patient therapies.

A Historical Perspective

The technological backbone of the vaccine can be traced back to advancements made in Mooney’s lab at the University of Michigan during the late 1990s. Here, he pioneered a gas foaming technique to fabricate porous structures meant for protein transport, initially aimed at tissue engineering.

At that time, Mooney envisioned using these structures to deliver growth factors to enhance cell transplantation, a concept that gradually matured into the idea of a cancer vaccine. This transition took place after he joined Harvard in the mid-2000s and began discussions with doctoral student Omar Ali about potential vaccine applications.

“We developed this as a way of gently encapsulating proteins in this polymer,” Mooney explained. Their collaborative journey led to early mouse studies that confirmed the vaccine's potential efficacy against various cancer types. “We generated significant immune responses in different models of tumors, suggesting we had uncovered a valuable therapeutic strategy,” Mooney added.

Clinical Trials and Challenges

As preparations took off for the human trials of WDVAX in 2013, it became evident that rigorous work was needed to standardize the technology. Doherty’s role was central in ensuring the process was replicable, a fundamental requirement for medical product development.

In collaboration with 18 specialists across multiple fields, including regulatory affairs, Doherty led the team through challenges associated with preparing the clinical trial application for the Food and Drug Administration (FDA). Managing a multidisciplinary approach, the team worked alongside Hodi and his clinical teams at Dana-Farber Cancer Institute, who conducted the actual clinical trials.

The Phase 1 WDVAX trial involved 21 patients with advanced melanoma. Patients were enrolled methodically to monitor safety, ensuring that adverse reactions were addressed promptly. The vaccine is ingeniously delivered via a surgically placed, sponge-like tablet that releases tumor proteins into the body, stimulating an immune response.

Technicians at the Connell and O’Reilly Families Cell Manipulation Core Facility prepared the vaccine by processing patients’ tumor cells to create a lysate. This lysate, combined with elements designed to kickstart an immune response, effectively informed the body about the threat posed by tumors.

While the trial yielded some positive safety data, including immune responses, six instances of death due to cancer progression sparked a critical reflection on manufacturing timelines and efficacy. The individual vaccine preparation for each patient led to lengthy production times, raising concerns for patients facing aggressive disease progression.

Future Directions: Improving Vaccine Efficacy

Despite the setbacks, researchers remain committed to enhancing vaccine efficacy. They noted increased levels of checkpoint proteins that inhibit T cell activity against cancer cells, suggesting potential synergies with checkpoint blockade therapies, which could bolster T cell responses.

In 2015, Mooney’s lab ventured into more versatile vaccination technology, developing an injectable version of the vaccine using silica rods. These rods assemble into a bioscaffold capable of sustaining the same functions as the original porous versions, offering a streamlined administration pathway more conducive to widespread clinical application. “We recognized the necessity for an injectable format as we weighed the logistics of routine vaccinations,” Mooney explained.

Turning Vision into Reality

Motivated by the exciting potential of their work, Doherty launched Attivare in 2021, bringing together several Wyss Institute colleagues. The initial phase of startup life came with challenges, particularly from pandemic disruptions. However, the company eventually secured $7.7 million in seed funding.

With a renewed focus on tackling infectious diseases, Attivare's platform is now aiming to leverage its immune-stimulating technology in novel ways. This includes an AI initiative designed to enhance understanding of individual cancer responses, a step that could prove pivotal for the future of personalized medicine.

Prospective funding opportunities add to the excitement. Doherty articulated hopes to raise $20 million to $30 million to develop the AI-Oncology Program further this year. The overarching philosophy at Attivare aligns closely with insights from Wyss Institute founder Hansjorg Wyss: pioneering technology must reach the patients who need it.

“Great technology that doesn’t make it to patients isn’t truly impactful,” Doherty concluded, capturing a commitment to translating scientific innovation into real-world medical solutions.