By Frank Bedu-Addo, Ph.D., and Gregory Conn, Ph.D., PDS Biotech
Immunotherapies offer the potential to attack cancer cells on two fronts: “unmasking” cancer cells that are unrecognized by the immune system and leveraging the power of T cells — our bodies’ “assassins” — to successfully kill cancer cells. Checkpoint inhibitor therapies, for instance, reveal tumors that “hide” from the immune system. While checkpoint inhibitors have advanced cancer treatment and are the current standard of care for a number of cancers, they don’t necessarily help the body build T cells to attack the cancer. The ability to build up cancer-attacking T cells in cancer patients remains a major limitation of current immunotherapy approaches. In addition, tumors utilize multiple mechanisms to evade detection by the immune system.
As we endeavor to develop “next generation” immunotherapies that overcome immune suppression and activate T cells to attack and kill cancer, we recognize that it is a challenging process where multiple strategies and viewpoints are necessary to develop drugs and combinations of drugs that may provide the highest likelihood of success. Along the way, particularly with our lead product PDS0101, an immunotherapy targeting human papillomavirus (HPV)-positive cancers, we’ve learned several lessons.
1. Ensure You Have An Experienced And Collaborative Team
The complexity of developing innovative therapies in an early-stage biotech environment demands a great deal of expertise and collaboration. Finding partners is important, but you need to bring together all of the relevant skillsets in some fashion during the development. We have hired, worked and collaborated with, leading protein chemists, tumor biologists, oncologists, and immunologists to understand and optimize how the technology works, to validate and corroborate results, and to help shepherd our technologies through early development. These technologies are now progressing through clinical trials with an eye toward potential commercialization.
2. Do Your (Data) Homework
Many biotechs and pharma companies have attempted to improve cancer treatment outcomes by developing cancer-fighting immunotherapies. In several types of cancer, checkpoint inhibitors have provided a significant advancement over the prior standard of care — usually chemotherapy or radiation — by unmasking tumors that are evading detection by the immune system. It is important to recognize that checkpoint inhibitors work by exposing the tumors to the body’s immune system. Without a robust army of T cells to attack the exposed tumor, cancer may continue to grow. For example, only about one in five patients with recurrent or metastatic HPV-positive head and neck cancer respond to checkpoint inhibitor therapy. There remains a significant need to build upon the success of checkpoint inhibitors by enabling the patient’s immune system to generate potent tumor-attacking killer T cells.
While targeted immunotherapies hold great potential, many early cancer vaccines that delivered promising data in mouse models could not replicate the same success in human studies. Often, the disappointing lower-than-necessary levels of effective killer T cells that could recognize, attack, and shrink tumors were due to the fact that the mechanisms by which the technologies worked in mice did not necessarily apply to humans. Even when they did, the larger size and blood volume of humans mitigated the ability of the technologies to induce similar results.
With this knowledge, we developed our technology to be less dependent on inter-species scaling. It was developed to be taken up by key cells of the immune system from the site of injection and then migrate to the lymph nodes, where it activates the patient’s own immune system to generate tumor-attacking killer T cells. This approach also limits broad exposure of the immunotherapy and related cytokines in the bloodstream and, therefore, minimizes the risk of adverse events.
We decided to approach our early development programs with a high level of objectivity as well as a healthy amount of skepticism. Upon designing our technology platform and the resulting immunotherapy products, we further studied the science behind our platform under various conditions, stress-tested the technology, and studied it in head-to-head comparisons with competing approaches until we were convinced that it met the criteria for potential clinical and commercial success and that external validation was warranted. We then partnered with academic and industry leaders to validate our technology and made sure we understood the mechanisms by which our immunotherapies worked and that these mechanisms translated to humans before we progressed into human clinical testing. Extensive preclinical testing was necessary to maximize the potential for clinical success.
At PDS Biotech, our early human clinical data and preclinical data suggest that we have developed an immunotherapeutic platform technology with the potential to improve upon current standards of care for patients with HPV-positive cancer, which includes anal, cervical, head and neck, vaginal, and vulvar cancers. We believe that good science coupled with the rigorous preclinical development program enabled a good characterization and optimization of the platform and product ahead of clinical testing in cancer patients.
3. Cultivate Fruitful Partnerships
Once our work resulted in an experimental drug, it took a great deal of persistence — evangelizing about the science — to get the attention of scientific leaders. Skepticism by experts toward our novel approach to T cell activation was part of the process of introducing new ideas in a field where limited success has been documented. We introduced Jerold Woodward, Ph.D., a tumor immunologist at the University of Kentucky’s College of Medicine, to our platform and the early preclinical data from our lead product. He became a collaborator with PDS Biotech to continue to develop PDS0101 and other pipeline products.
We also established a collaboration with the Cancer Vaccine Division of the National Cancer Institute. Validating the science through expert third-party collaborators and ensuring that the data could be replicated by multiple expert labs was an important part of the process, through which we as founders and leaders in the company could gain even more confidence in the data. This enabled us not only to confidently progress into the clinic but also initiate the process of becoming a publicly traded company and begin talking to investors about the company. Importantly, obtaining additional validation through third-party partnerships increased confidence in the results.
4. Don’t Forget To Put Patients First
Safety of cancer immunotherapies is a key consideration in the development of innovative T cell therapies. For example, some immunotherapies can sometimes trigger off-target toxicities such as cytokine storm syndrome, a life-threatening condition characterized by the release of inflammatory proteins called cytokines into the circulating blood at a level that is dangerous and potentially lethal to patients. Other types of safety concerns are also common with cancer drugs and immunotherapies.
We also recommend that biotechs take time to consider target group appropriateness. One of the fundamentals of medicine is getting the right treatment to the right patient at the right time. The best treatment could still appear weak in the wrong target group. In our work at PDS Biotech, PDS0101 builds and directs a T cell attack against the most oncogenic or cancer-causing type of HPV. The vast majority of HPV-associated cancer patients are positive for HPV16. Our target group for PDS0101 is therefore HPV16-positive cancer patients. For many HPV-positive cancer patients, using a combination therapy that is clinically effective that preserves the quality of life is essential.
Various types of immunotherapies are being developed. The field has advanced significantly, and immunotherapies have made incredible leaps forward in overall outcomes when they are administered to the right patients. We’ve learned a lot of powerful lessons since we started PDS Biotech and embarked on our path to create an immunotherapy platform that has the potential to improve patient outcomes. Good science, a great team, and a healthy dose of skepticism are necessary elements for drug development success. Having a rigorous intellectual approach to developing drugs is important, but having the heart to put patients first is a huge motivator to making this mission fulfilling as we work to transform the treatment of cancer.
About The Authors:
Frank Bedu-Addo, Ph.D., has served as cofounder, president, and CEO of PDS Biotech since its inception in 2005. He has experience successfully starting and growing biotech organizations and has been responsible for the development and implementation of both operational and drug development strategies, including supervising and managing both large and emerging biotech companies. Bedu-Addo obtained his M.S. in chemical engineering and Ph.D. in pharmaceutics from the University of Pittsburgh.
Gregory Conn, Ph.D., is cofounder and chief scientific officer of PDS Biotech. He has more than 35 years of drug development expertise, including development of antiviral and anticancer drugs through to commercialization. He is a graduate of the Albert Einstein College of Medicine, where he obtained both his M.S. and Ph.D. discovering novel angiogenic molecules in the human brain. Conn has expertise across all phases of the drug development process, including FDA and regulatory requirements, and is the co-inventor of eight drug patents.