CAR-T Therapy: A Novel Approach to Cancer

The very best part of working in Silicon Valley Bank’s Life Science and Healthcare Practice is the ability to watch breakthrough innovations unfold, in real time, across our client set and their respective patient base. While it is unusual to see step-change developments in disease management, in oncology (cancer research), at least in some patient subsets, we have seen just that with a new modality of treatment known as CAR-T therapy. This area of research shows promising signs of curing cancer in patients who have few options remaining.

First, an introduction to immuno-oncology

Before diving into what CAR-T therapy is, let’s start with a broader classification: a field of research called immuno-oncology (I/O). This set of tools and approaches is geared toward having a patient’s own immune system do what it is programmed to do naturally — fight off unwanted guests. By focusing on this process, researchers either stimulate the immune system directly (step on the gas) or work to inhibit the mechanisms that suppress it (apply the brakes). Scientists have a variety of tools at their disposal to accomplish this, and the idea is to give your body the boost it needs to help defend itself, either by helping the body detect the cancerous cells or fighting them off directly.

There is no shortage of interest in I/O. In fact, former Vice President Joe Biden’s Cancer Moonshot 2020 program called for the creation of a Cancer Immunotherapy Translational Science Network simply to oversee all the work going into the field. With all of the attention that the space has garnered, it is not surprising to see the sizeable investments, company formations and exits that have taken place. There are nearly 1,000 clinical trials underway and, from 2014–2016, there were over 300 individual financing rounds in the sector, accounting for $8 billion in investment, according to Tracxn research. The first I/O drug, YERVOY, designed to treat melanoma, only arrived on the market in 2011. There are now five I/O drugs available commercially — but none are based on CAR-T therapy.

Welcome to CAR-T therapy

Chimeric antigen receptor (CAR) T-cell therapy first hit primetime in 2014 when the University of Pennsylvania (disclosure: I am a proud Quaker) published results from a 30-patient trial in acute lymphoblastic leukemia (ALL) — the most common type of childhood cancer. Ninety percent of patients, who generally used this as their last line of defense, experienced complete remission. This is as good as it gets for cancer treatments: No evidence of cancer remained following a single infusion of therapy. With rapid, complete and durable responses, the trial was a defining moment for CAR-T therapy. 
 But as it turns out, CAR-T therapy is tricky stuff and still very messy.

What is CAR-T?

It is easier to approach this intimidating acronym from the end. Let’s flashback to your high school biology class and remember that T-cells are a type of white blood cells that float around your body as part of the immune system. They come from your thymus gland (hence the “T”) and are situated near the top of your sternum. Scientists take these T-cells out of your body via a process much like giving blood (leukapheresis); then, they take the T-cells back to their lab. Here they attach a binding end of an antibody, which acts sort of like a magnet, to help with directed targeting. This process effectively gives the T-cell a super boost.

After some time to grow in the lab, the CAR-T super cells are injected back into the same patient. This is called autologous therapy, and it has some pretty obvious commercial and manufacturing limitations: It’s slow, it’s expensive, it’s not scalable and it’s tough to regulate.

The reintroduction of the T-cells is not unlike an organ transplant. Many patients receive chemotherapy while they are waiting for the new cells; this subdues the immune system and gives the new cells more room to reproduce.

Assuming the body responds, what happens next can be terrifying. From the time that the CAR-T cells are administered and up to three weeks later, the patient is at high risk of developing cytokine-release syndrome. Cytokines are immune-signaling proteins that notify the body that the immune system is being activated, which is the desired effect. However, if cytokines are dumped into circulation too rapidly, this can cause a cytokine storm, which can result in death. In fact, several high-profile clinical trial deaths have occurred in the quest to bring these therapies to market. Neurotoxicity is also a concern; several trials have been halted by the FDA due to these serious side effects. One company’s lead drug was scrapped due to recurring neurotoxicity issues.

In the best cases, if it all works as planned, the patient will suffer through some rough side effects, but the T-cells will be on a beneficial rampage through their blood. The newly engineered cells will circulate through the patient, fitted with an antibody arm that can latch onto the cancer cells in a way they couldn’t before.

Promising data

While the outcomes from CAR-T therapy aren’t always ideal, the results speak for themselves. Keep in mind that the patients receiving this treatment are the sickest of the sick and have generally exhausted more traditional treatment plans, which is why enthusiasm can be felt throughout the industry.

Recent preliminary results from a Novartis study in 87 pediatric patients with acute lymphoblastic leukemia showed an 82-percent response rate. In February, Kite Pharma reported top-line data in a trial of 101 patients with aggressive non-Hodgkin’s lymphoma (NHL); the findings showed complete response rates nearing 40 percent at six months post-infusion. This was one of the first duration studies to read out with data.

An often-overlooked, though key, element of this therapy is that, since these are your own cells, they divide and live in your body, resulting in a lasting response rarely seen with other treatments. Many cancer treatments can slow or stop the cancer for only a short period before the patient relapses and the cancer returns. Remember — what makes this therapy so unique is that unlike most drugs, which target specific markers or treat specific symptoms, this treatment manipulates the body’s immune system to do the targeting and killing of the tumor on its own.

Next-gen CAR-T therapy

As with any new technology, work has already begun on improving it. We are seeing novel advances to the initial constructs used in CAR-T therapy to help address the toxicity, manufacturing burden, commercial and pricing hurdles and other barriers that exist in making CAR-T therapy more widely adopted. CRISPR is being applied to more precisely engineer the CAR-T cells. Companies like Fate Therapeutics are using their technology to create “off the shelf” T-cells that would not need to be derived from the patient for CAR-T therapy preparation. Third-party healthy-donor T-cell therapies (known as allogeneic, as opposed to autologous, as discussed above) have seen their first successes, with Cellectis applying this treatment successfully to two infants who did not have enough T-cells left for the traditional CAR-T approach. Cell Design Labs is working on new ways to moderate the T-cells by being able to turn them on and off with the goal of reducing toxicity.

True success

There are currently over 120 CAR-T therapy trials underway, 60 of which are being conducted in China, and many of the trials are focused on cancers with very limited treatment options. This is most acutely the case in pediatric cancer patients, historically an underserved population, with no traditional treatments left. The potential of a “hail Mary” — a single infusion CAR-T therapy — has researchers and parents desperately trying to push these therapies forward.

One little girl, Layla, was suffering from acute lymphoblastic leukemia and had already gone through chemotherapy, a bone marrow transplant and several novel drug treatments, all of which had no impact. She was going to be moved to palliative care to keep her comfortable until she died. Instead, in 2015, her physician and parents decided to try a new donor-cell-derived CAR-T treatment. After getting the cells around the time of her first birthday, Layla went into remission, with no trace of leukemia found in her blood or bone marrow. Nearly two years later, she is home, with no trace of her original cancer remaining.

This is more than a modest improvement in cancer treatment: The sickest patients are being cured. While we have much to discover about this new treatment, CAR-T therapy is bringing hope back to those patients who may have lost it.



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