Surveying great inventors and businesses
Build with Axial: https://axial22.axialvc.com/
Axial partners with great founders and inventors. We invest in early-stage life sciences companies such as Appia Bio, Seranova Bio, Delix Therapeutics, Simcha Therapeutics, among others often when they are no more than an idea. We are fanatical about helping the rare inventor who is compelled to build their own enduring business. If you or someone you know has a great idea or company in life sciences, Axial would be excited to get to know you and possibly invest in your vision and company . We are excited to be in business with you - email us at email@example.com
Edgar Engleman is a pror of pathology and medicine at Stanford. Not only is he a great inventor but has been involved in countless biotech companies and whose scientific career shows the power of curiosity-driven research. The Engleman Lab has been at the center of understanding the role of the immune system in cancer. By the 1990s, various groups had observed high levels of immune cells within tumors and data suggested they were reprogrammed to promote cancer growth. This ultimately led to our current conception of the tumor microenvironment (TME). Around this time, the Engleman and later this lab started initial work around engineering dendritic cells to present tumor antigens to T-cells and activate the latter to potentially clear tumors. Versus the status quo of the era, this research was viewed as inconceivable. How could immune cells be removed from a patient, modified, then reintroduced back into the same patient? This early work ultimately proved that immune cell reprogramming in the TME was reversible and that cells can be engineered ex vivo to target cancer.
From this research, led to the invention of the first approved personalized immunotherapy, Provenge developed by Dendreon, a company co-founded by Engelman. Dendreon did not scale but planted the seeds for companies like Juno Therapeutics, Kite Pharma, and the entire cell therapy field to emerge in the 2010s. Hans Bishop, CEO of Juno was previously COO of Dendreon. Often a company, a market leader, enables others. The leaders from that batch enable a new class. And so on. Beyond his academic work, Engleman also co-founded companies from Cetus (a legendary biotech; PCR was invented there) to Bolt Biotherapeutics and Genelabs. His father, Ephraim Engleman was a rheumatologist at UCSF, likely set the seeds for the younger Engleman’s career focused on using science to help patients. His oral history does a good job at going deep into Engleman’s life’s work.
1. “I remember where I was when Kennedy got shot. I remember where I was in the ’89 earthquake. And that’s about it, those three things.”
What a quote. The third memory is the approval of Provenge. Also reminds me of a Guns N’ Roses lyrics from Civil War:
“And in my first memories
They shot Kennedy
I went numb when I learned to see
So I never fell for Vietnam
We got the wall of D.C. to remind us all
That you can't trust freedom
When it's not in your hands
When everybody's fightin'
For their promised land
I don't need your civil war”
2. “We thought, and immunologists taught, that it wasn’t just that our immune systems are reluctant to react to cancer; they can’t, because all of the B-cells and T-cells that are capable of recognizing self have been physically removed and destroyed.”
In the 1990s, common scientific wisdom taught that immune cells won’t be able to recognize cancer cells. Because they would have been removed in the thymus if they were able to. This is why Engleman’s work at the time is a great example of the power of curiosity in research. Despite the pushback, exploring the role of immune cells found within tumors led to new discoveries around the TME and led to the approval of CAR-T cell therapies ~2 decades later.
3. “It’s almost impossible for the immune system to make that distinction without a little kick in the butt.”
However, for a T-cell to recognize a cancer cell versus normal tissue, some level of engineering at the time. In the 1990s, that initially meant loading dendritic cells with tumor antigens to present to T-cells. Around the same time, 1993, the original work that laid the ground for chimeric antigen receptors (CAR) was done (plasmid image of one of the first CARs below). This is what succeeded in the clinic and market - engineering T-cells directly to target tumor antigens.
4. “I was taught that the immune system was incapable of recognizing cancer because cancers are comprised almost entirely of the same substances as normal tissues. The immune system is trained to avoid attacking ‘self’.
As recently as 10 years ago, there was almost total skepticism about the prospects of immune based therapy for cancer.
However, I disagreed with these beliefs and thought the immune system could potentially be exploited to treat cancer. I hypothesized that we could manipulate dendritic cells, which are powerful immune stimulating cells, to induce an anti-tumor immune response.”
Another quote reinforcing the power of pursuing interesting scientific questions regardless of what others think. As long as the experiments are designed well, whether or not they produce positive results is irrelevant. The pursuit of something different is valuable in itself.
5. “Trainees inspire me. Students and post-docs are generally fearless, and they are the reason why my lab has a long history of undertaking high-risk projects.”
Young scientists, and people in general, are often willing to take more social risk than established individuals. So wisdom + social risk often leads to outsized results in science, business, and life.
6. “For many years, the focus of cancer research was on studying only the tumor cell, or the “seed,” rather than the “soil” environment where it grew. However, cancer results from complex interactions between tumor cells and the host environment, including immune cells. We need to understand the various forces in the “soil” to optimally treat cancer, which requires a systems biology approach.”
7. “Basically I had a choice: I could either go work for the company or not. I chose to stay at Stanford and continue doing discovery work, and I’m glad I did.”
Everyone should probably focus on being the best on something. For Engleman that meant doing scientific research. And engaging with others to build companies around his lab’s work. The trick for every inventor is retaining ownership of the companies that use their IP.
8. “[Work to find] a way of targeting [immune] cells in the body, and doing better than we were doing manipulating the cells outside the body—not just from a cost perspective but from a potency perspective.”