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David D. Tran, MD, PhD – Brain Cancer Science Talk (Episode 6)

An Open-Minded and Curious Physician/Scientist Follows the #Data to Innovate a Compelling Protocol for Treating Gliomas

Click here for David Tran’s “Meet the Team” profile on MissionGBM

Ever since the MissionGBM “Brain Cancer Science Talk” video interview series was announced, readers have been asking, “When is David Tran’s interview going to post?”

We are pleased to reply, “The wait is over”.

Formally, David D. Tran, MD, PhD is Chief of Neuro-Oncology and Co-Director of the Brain Tumor Center at the University of Southern California in Los Angeles.  To the MissionGBM community, however, David is much more.  For the past 2.5 years, David has been a valued partner and member of a global Team that has relentlessly sought to advance brain cancer research and clinical translation in a manner that we typically do not see within the Neuro-Oncology field.  He is a rigorous and careful scientist, who never accepts mediocrity and always insists on letting the #Data speak.

David is also a genuinely good person, who will find a way to rearrange his busy schedule in order to speak with a patient, or engage in peer-to-peer consulting with other Neuro-Oncologists wrestling with challenging cases for which there are few treatment options.

Results That Matter: 2-THE-TOP…And Beyond

Dr. Tran is a soft-spoken person, who prefers to let his work do the talking.  Over several years, he patiently put together the 2-THE-TOP protocol (2TT) that was tested in a Phase 2 clinical study (see here and here).  Moreover, David and his colleagues did the hard work of elucidating the underlying molecular biology and immunology that serves as the elegant scientific foundation for the 2TT protocol (see here).  All of the work occurred against a backdrop of significant skepticism within the Neuro-Oncology field regarding the utility of the Tumor Treating Fields (TTF) technology that is integral to the 2TT regimen.  Unlike most of his peers, Dr. Tran did not simply dismiss TTF as “pseudo-science”, but instead, he chose to follow the #Data to uncover a powerful mechanism of action that linked TTF-driven disruption of the mitotic process in cancer cells to the uniquely effective anti-cancer capabilities of the activated human immune system.

Dr. Tran’s #Data revealed that the 2TT technique invoked three vitally important biological actions that are key to effective solid tumor immuno-oncology therapies:

  • Present the full spectrum of Tumor-Associated Antigens (TAAs) to the antigen processing cells of the immune system.

  • Cause the Tumor Micro-Environment (TME) to flip from immunologically “Cold” (immunosuppressed) to “Hot” (inflamed); thereby, providing an attractive target for immune system engagement.  Further, ensure that the immune system activation is focused on the tumor so as to minimize spillover into systemic immune-related toxicities.

  • Prevent the responding anti-cancer, cytotoxic immune cells from becoming exhausted within the TME, and losing their ability to kills cancer cells expressing TAA.

Collectively, the 2TT protocol functions as an in situ vaccination technique that is personalized to an individual’s tumor.  Such is the Holy Grail of cancer immunotherapy, which is rarely achieved for solid tumors.

The Planned Serendipity of Good Science, Its Clinical Translation and the Power of Working on a Multi-Functional Team

In the linked video interview with Dr. Tran, David and I describe how we first met, and our collective initial skepticism regarding the prevailing official explanation of the mechanism behind the TTF-driven Objective Responses that were occasionally observed. We discuss the multi-year path that David followed to design the 2TT protocol, and then carefully work out the underlying science to validate his original scientific hypotheses.  We talk about what has been learned over the past few years regarding clinical translation for GBM/HGG cases both within the formal 2TT Phase 2 trial as well as the dozens of MissionGBM cases that have employed the core 2TT protocol in community practice.  We consider findings that begin to sketch out potential biomarkers for patient selection and Objective Response prediction.  We go on to chat about the reality of irAEs in any protocol that employs immune checkpoint inhibitor medicines like pembrolizumab (Keytruda®), and how the Team was expanded to involve experts like Michael L. Dougan, MD, PhD (see here and here) in order to mitigate irAEs and keep patients safely on protocol.  Finally, we show actual #Data for Julie’s Journey from her original GBM diagnosis in Dec-2021; to her initial setback upon first utilization of the baseline 2TT protocol (Mar-2022); through the months of careful work to add prophylactic infliximab to the core 2TT regimen in order to allow safe rechallenge with pembrolizumab (Jun-2022); and ultimately all the way to a Complete Response (Dec-2022), which has proven to be durable for more than one year.

Many Thanks to David D. Tran, MD, PhD for his leadership and rigorous science in the service of brain cancer patients all over the world.


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