The Bio + Health Newsletter

Bio Monthly Newsletter: August 2019

a16z editorial

Posted August 30, 2019

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What’s Next in Dx/Rx/Px

Andy Tran

New CAR T tools for new targets
This month we saw another powerful engineering development in CAR T therapy—one of our strongest new tools against cancer. In CAR (chimeric antigen receptor) T-cell therapy, T-cells are harvested from a patient; then a specific receptor on the T-cell is “engineered” to recognize certain cell-surface proteins of cancer cells. When the CAR T-cells are re-infused into the patient’s body and encounter those targets on cancer cells, the engineered receptor drives a swarm of T-cells to the cancer cell, the T-cells “attack”, and the cancer cells are destroyed. In short, our own immune system can be “reprogrammed” to shut down the cancer—which can result in an almost miraculous eradication.

But this therapy’s success has so far been limited to only blood-based (i.e., liquid) cancers like non-Hodgkin lymphomas and leukemias. One of the holy grails in cancer therapy has been using CAR T drugs to treat solid tumors (prostate, breast, lung, etc.), which represent over 90% of cancers. Solid tumors are very difficult to treat this way because not all of the tumor cells express a clear target that a T-cell can go after. A “typical” CAR T-cell can usually only go after one target, and that target often has to be very specific for the tumor, or they could severely damage another healthy organ that expresses that target.

Recently, a team led by Dr. Marcela Maus at MGH made a major advancement towards utilizing CAR T for solid tumors (in this case, glioblastoma). Though glioblastoma has a specific mutated protein called EGFRvIII that can be targeted, the problem is that it’s only expressed in a small fraction of the cancer cells. In effort to tackle the entire solid tumor, the team engineered the cell to take advantage of multiple “imperfect targets”, targeting a second antigen at the same time. But since this second antigen (EGFR) is also present in many other cells in the body, drugs targeting that protein could cause serious side effects. So Maus and team engineered a CAR T-cell that is essentially activated in the brain. When it gets into the brain—and only then—the CAR T-cell secretes a second type of modality, called a “BiTE” (bi-specific T-cell engager), in essentially a one-two punch to the cancer cell. When they tested this, the modified BiTE-secreting CAR T-cells completely eliminated glioblastoma tumors in over 80% of their mouse models.

The biggest implication of this work is not just the one-two receptor action where CARs and BiTEs can be combined to mitigate antigen heterogeneity. It’s also the innovation that CAR T-cells can be engineered as “living” vehicles, for the local delivery of biologically active molecules like BiTEs, to a specific tumor microenvironment—and leave other healthy tissues alone. This marks a big shift in our understanding of what we can engineer CAR-T cells to do, where, and when—bringing us one step closer to being able to more precisely eradicate solid tumors with the human body’s own immune system.

Andy Tran is a Principle at Matrix Capital Management Company.

Bio as a Platform

‘Tis the season for vegan
2019 was the summer of ‘meatless meat’, as partnerships between big fast food chains and alternative meat startups began to gain real momentum. KFC just announced their testing of a “Beyond Fried Chicken” sandwich; Burger King their nationwide rollout of the “Impossible Whopper”; Subway a “Beyond Meatball Sub” for the fall; Dunkin’s Beyond-based sausage sandwich in July. These food franchises now join the ranks of White Castle, Applebees, Qdoba, and many more in providing alternative meat options on their menus. Restaurants like these partnerships because it reduces their burden to innovate, and drives foot traffic into their stores—and the primary customer buying these products, it turns out, is “regular person, eats meat, wants to eat a little healthier each day.”

Product type is really the key differentiator in this space (not just beef vs chicken vs fish, but meatball vs sausage vs burger). So each product has a unique go-to-market strategy, with different opportunities, challenges, and partnerships. Proving health benefits is the next big fish to fry, since that’s an important driver for consumers and there’s some evidence emerging that these burgers may not be significantly healthier than the meat originals. Ultimately, it’s the molecules that make up a final food product that make it healthy or not.

So far the market has mainly seen meat products, but we will very soon see this in other animal products as well—dairy, gelatin, eggs, even oil-based home goods. The third wave of this innovation will be particularly interesting, when manufacturing begins to incorporate materials traditionally produced from animal by-products, like certain plastics, rubber, waxes, soaps, and more.

Special excerpt:

Marc Andreessen on “The Evangelist Sale” in healthcare:
Healthcare is an industry where innovation is particularly hard—existing systems are not only complex, but have good reason for being so. Bringing change to to this culture can be an uphill climb.

Listen to this short excerpt from our recent episode of the a16z Podcast, “Software Has Eaten the World… and Healthcare is Next,” where Marc addressed a question about how to introduce innovation into the industry:

“We’re here today in a place that’s known as a center of innovation. But many of us have to go to be agents for innovation and change in industries that aren’t necessarily as open to it. What is your advice for that—how do you think about doing something innovative, that you believe in, that you think will work, when others might say, oh, we’re more traditional, this is the way things are done?”

Agents of Change: How Do You Innovate From the Inside?

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