For all of the wondrous potential of immunotherapies, there have been some notable obstacles in the early goings. Engineering immune cells to attack cancerous tumors can lead to solid results shortly after administering a dose, but for many patients the effects wear off once rapidly mutating tumor cells acquire new defense mechanisms.

Cellectis (NASDAQ:CLLS) thinks it may have a partial solution. In mid-November, the gene editing company published the results from a proof of concept study for its "smart" immunotherapy approach. Is the technique the future of cellular medicine?

Image source: Getty Images.

Today, cellular oncology therapies genetically engineer immune cells to bolster their safety and efficacy as a cancer treatment. There are T cells, natural killer (NK) cells, tumor infiltrating lymphocytes (TILs), and others. They're often engineered with chimeric antigen receptors (CARs) or T cell receptors (TCRs), which allow them to home in on and suppress specific genes in cancer cells.

While current-generation CAR T cells or CAR NK cells are capable of mounting formidable attacks on tumors at first, treatment responses aren't durable for all patients. That's because cancer cells mutate to rely on different proliferation genes, or secrete new molecules into the tumor microenvironment that neutralize immune cells. Meanwhile, overstimulating the immune system can reduce the potency of immune cells and lead to devastating side effects, such as cytokine release syndrome.

That prompted Cellectis to design "smart" CAR T cells capable of adapting to changes in the tumor microenvironment. In a proof of concept study, the company utilized synthetic biology concepts to rewire genetic circuits in three different genes of the initial T cells.

One edit made the immunotherapy more potent, but in a controlled manner to reduce off-target toxicity. The other two edits imbued CAR T cells with the ability to secrete inflammatory proteins inside the tumor microenvironment in proportion to the concentration of cancer cells.

In other words, the smart CAR T cells only asked for help from the rest of the immune system when it was needed most, which increased the anti-tumor activity of treatment and made native immune cells less likely to become neutralized. That should reduce the likelihood of triggering cytokine release syndrome, the most common (and potentially fatal) side effect of cellular medicines, which is caused by high concentrations of immune cells.

The study was conducted in mice, which means the safety and efficacy observations can't be extrapolated into humans. But that wasn't the point. The proof of concept demonstrates that the basic idea of engineering tightly controlled genetic circuits into immunotherapies is feasible. It could even allow multiple genetic circuits of the same drug candidate to be tested against one another in parallel, hastening drug development and lowering costs. Is it the inevitable future of cellular medicine?

Image source: Getty Images.

Gene editing tools are required to engineer immune cells. In fact, immunotherapies are the lowest hanging fruit for gene editing technology platforms today. It's simply easier to engineer immune cells in the lab (ex vivo) than it is to engineer specific cell types in the complex environment of the human body (in vivo).

That explains why nearly every leading gene editing company has immunotherapy programs in its pipeline. Coincidentally, all of the leading drug candidates in the industry pipeline are off-the-shelf CAR T cells engineered to treat CD19 malignancies such as non-Hodgkin's lymphoma (NHL) and B-acute lymphoblastic leukemia (B-ALL), regardless of the gene editing approach used. The smart CAR T cells designed by Cellectis targeted CD22 malignancies, but the approach could be adapted to CD19 antigen.

Developer(s)

Drug Candidate

Gene Editing Approach

Development Status

Cellectis and Servier

UCART19

TALEN

Phase 2

Precision BioSciences (NASDAQ:DTIL)

PCAR0191

ARCUS gene editing

Phase 1/2

CRISPR Therapeutics (NASDAQ:CRSP)

CTX110

CRISPR-Cas9

Phase 1/2

Sangamo Therapeutics (NASDAQ:SGMO) and Gilead Sciences (NASDAQ:GILD)

KITE-037

Zinc finger nuclease

Preclinical

Data source: Company websites.

Will these companies eventually turn to "smart" immunotherapies with regulated genetic circuits? It does seem inevitable, especially if the approach can reduce or eliminate cytokine release syndrome and enable more durable responses.

For example, Cellectis reported that all seven patients taking part in the phase 1 trial of UCART19 suffered from at least grade 1 cytokine release syndrome, which caused complications that led to the death of one patient. Five of the seven patients achieved molecular remission, but one relapsed (and remained alive) and one died. To be fair, all patients taking part in the trial had advanced, heavily pretreated B-ALL.

Precision BioSciences has encountered similar obstacles in an ongoing phase 1/2 trial of PBCAR0191. The company's lead drug candidate was administered to nine patients with NHL or B-ALL. Three cases of cytokine release syndrome were reported, but all were manageable. Seven responded to treatment, including two that achieved a complete response, but three eventually relapsed.

CRISPR Therapeutics recently began dosing patients with CTX110 in a phase 1/2 trial that will eventually enroll up to 95 individuals, but initial results won't be available until 2020. Sangamo Therapeutics and Kite Pharma, a subsidiary of Gilead Sciences, are plowing ahead with zinc fingers,but are still in preclinical development.

Investors seem pleased with most of these gene editing stocksright now. After all, despite the obstacles, current-generation cellular medicines are delivering impressive results in patient populations with relatively few options. But upcoming data readouts could easily differentiate the pack. That could increase the need to invest in augmented capabilities, such as smart immunotherapies.

There's plenty of untapped potential in cellular medicine. Today, companies are developing drug candidates with engineered CARs and TCRs designed to test hypotheses about the function of immunotherapies. As approaches find success, measured in safer and more durable responses, the next layer of complexity will be added in an effort to find even more successful therapies. And the cycle will continue.

Therefore, it seems inevitable that the field of cellular medicine will turn to smart immunotherapies with more complex genetic edits, much like the field quickly embraced the need for engineered immune cells and off-the-shelf manufacturing processes. That said, the immediate focus for Cellectis and its peers is building a stable foundation -- and those efforts have only just begun.

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Did Cellectis Just Provide a Glimpse of the Future of Cellular Medicine? - The Motley Fool

Patients with multiple myeloma have a lot to look forward to in the treatment space thanks to precision medicine, but one treatment option alone will not cure the disease.

At the 2019 CURE Educated PatientSummit on Myeloma in Charlotte, North Carolina, Rodriguez, director of the myeloma and plasma cell disorder program at Wake Forest University, had the chance to speak to numerous patients with multiple myeloma on the current treatment landscape of the disease and precision medicines role in it.

This year, Rodriguez also participated in the Multiple Myeloma Research Foundations Moving Mountains for Multiple Myeloma program when he took a 10-day journey through the South American region of Patagonia with other multiple myeloma survivors and specialists. This journey allowed Rodriguez to have intimate contact with patients who have multiple myeloma and talk with them about the future of treatment for the disease.

In an interview with CURE, Rodriguez explained the role of precision medicine in the treatment of patients with multiple myeloma and how he addresses common questions about it from patients.

CURE: How has precision medicine changed the landscape of treatment for patients with multiple myeloma?

Rodriguez: Precision medicine has changed the way we treat myeloma in many ways, and that not only means that we are finding new therapy that can target specific areas of the cancer cells, (allowing us) to have more effective therapy with less side effects, but it also means that we can actually tailor therapy to an individual patient.

It's not just that we're developing new drugs that are homing in on the cancer cells, but it also is that we're taking some time to individualize the care based on each patient's needs, each patient's requirements, and the cancer that each patient has. We do know that multiple myeloma is not a one-stop, everybody-has-the-same-type disease; everybody has different variants, and within a person, there's different subgroups of myeloma cells that needs to be targeted in a different way.

What are some of the questions about precision medicine that patients might have for you, and how do you address them?

One of the questions that normally arises whenever precision medicine, or personalized medicine, or targeted therapy all of these words are used interchangeably in clinic (comes up) is: Will a new treatment that targets a specific mutation cure my disease, if I have that mutation? And that's a very valid question, because you would think that if we've designed a therapy that can target a particular mutation that your cancer has, that we would eradicate the cancer.

Yet, the reality is, I don't think that targeting one particular mutation is going to be the solution to our problems. Myeloma is composed of many subgroups of myeloma cells within one patient.

So, combining precision medicine with a therapy that we already have and targeted immunotherapy that might give us a broader aspect of how we can target the cancer and have better control of it. Hopefully, by combining different targeted therapies with standard therapy, we might be able to eradicate the cancer. But the precision medicine or a single agent on its own is probably not going to be the solution for it.

What are some of the unique challenges from the use of precision medicine to treat patients with multiple myeloma?

One of the challenges of precision medicine in myeloma in particular is that myeloma tends to evolve as time goes by, and it's developing new mutations. And these new mutations can cause resistance to therapy. Even if we're using precision medicine that can target a particular mutation, if that cancer cell continues to evolve and mutate, maybe that particular mutation, or that target, might change as well, and then the therapy stops working.

That's a big challenge that we still have with precision medicine, that we need to figure out how we can factor that in whenever we're treating patients. So, resistance to therapy, despite (the use) of precision medicine, is something that we can potentially see.

What is the difference between DNA and RNA testing for patients with multiple myeloma?

The difference between DNA and RNA when it comes to cancer is a little bit different. We're using genes now to understand how cancer behaves. That's given us a lot of information about how we can potentially treat myeloma and how it normally behaves. A lot of doctors might say, Oh, I'm checking your DNA, or I'm checking your RNA to see what information we can get from it.

The main difference is, DNA is all the genes that we have in our body, and all the genes that are going to be in a cell and particular in a cancer cell. RNA are the genes that are actually used and expressed in those cancer cells. So not all the DNA is used. It's just the RNA portion that's going to be telling us what sections of the DNA are actually active and which ones are not.

Can you discuss some of the highlights from your keynote lecture at the 2019 CURE Educated Patient Summit on Multiple Myeloma?

The focus of the talk was on a few factors. One is that we've realized that treating myeloma patients it's not the same if I treat somebody here or if I treat somebody in a different state or in a different country. Humans are not all the same. We all are very unique. We all have very different characteristics and features, medical problems, social issues, environmental differences and walks of life. We cannot use one same treatment for all of us, because it's not going to be effective for all of us.

So, tailoring it for our different characteristics is one part of precision medicine. And then the other factor in my talk was the cancer itself. Myeloma is not just one cell type, where all the people who have myeloma are going to have the same characteristics. It's very variable, and within patients, there's variability, and there are different clones of myeloma cells in that same patient, and then each patient is very different in terms of how their myeloma is.

We've learned so much about cancer, and myeloma in particular, that we've now been able to identify different subgroups of myeloma cells within a patient, or between patients, that we can target and be more specific in how we treat. So, the goal of the talk was to let everybody see that whenever we are treating myeloma, we have to individualize the care to that particular patient.

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Precision Medicine Paves the Way for Exciting Treatment Combinations for Patients with Multiple Myeloma - Curetoday.com

For biotech, 2019 ended like the penultimate episode of a prestige TV show. We got answers to some weighty questions, but mostly, the year left a breadcrumb trail to some major reveals.

The IPO window stayed open, helping scores of companies go public. Futuristic therapies proved their worth in clinical trials, pointing to a new era in medicine. And the markets ended the year on a high, buoyed by a Food and Drug Administration that seems ever more flexible when it comes to approving new drugs.

Now, with 2020, well get the more important answers. Sure, theres a lot of public biotech companies now, but what if thats a bad thing? Yes, cell and gene therapies look transformational, but what if they never make any money? And since when is everyone so confident they understand whats going on inside the FDA?

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Here are three trends to watch in biotech in 2020, a year that looks to be laden with opportunities and stumbling blocks for the drug industry.

While every biotech startup is undoubtedly special in the eyes of the venture capitalists quoted in its press releases, 2020 could be a year marked by fatigue for the outside public.

More than 140 biotech companies have gone public since 2017, according to the analysts at Evercore ISI, and now theres upward of 500 of them trading on the Nasdaq. Keeping tabs on them all is essentially impossible, and its become fairly commonplace for biotech types to see the name of a given company for the first time by reading about its implosion.

Thats arguably a good problem to have in societal terms. More biotech companies means more efforts to treat human disease. But it could be problematic for the herd. Drug development remains an expensive proposition, and the majority of the biotech companies that went public in the past three years have negligible or nonexistent revenue. That means theyre going to have to go back to the market with follow-on offerings, and they may not like what they find.

According to Cowens biotech thermometer, a regular update on Wall Street sentiment, investors are increasingly selective when it comes to equity offerings, spooked by slumping IPO returns and a glut of supply. If that trend continues into 2020, some of those 500-plus biotech companies might need to look for other means of keeping the doors open, including mergers that thin the flock.

Much of the conversation around cell and gene therapies has focused on how much they cost, and understandably so. Two million dollars is, objectively, a lot of dollars. But the anxiety in biotech circles is a bit different: Is anyone going to make money on these things?

Take, for instance, CAR-T cancer therapy. For some patients, a single dose erases any trace of aggressive, otherwise untreatable cancer. For every patient, a single dose costs about $400,000. That sounds like a lot, but churning out a genetically engineered immune cell is hardly akin to widget manufacture. CAR-T companies dont disclose their underlying costs, but these therapies are understood to be low-margin products.

Theyre also considered commercial disappointments. The first two approved CAR-Ts, Kymriah and Yescarta, have underperformed analyst expectations to date. And that has stoked concern that a coming wave of gene therapies could face similar commercial difficulties.

Like CAR-T, gene therapy is costly to make, can be administered only at certain sites, and has made headlines for its six- or seven-figure list prices. Biotech companies and their investors have staked billions of dollars on the idea that such one-time treatments can become lucrative products. If that assumption is incorrect and the industry cant figure out how to make money in therapy, there could be a painful knock-on effect for biotech.

Handily, theres a one-company test case to follow in 2020. Novartis (NVS) sells a CAR-T in the form of Kymriah and a gene therapy called Zolgensma. Furthermore, thanks to a recent $9.7 billion acquisition, it will likely soon sell an RNAi treatment for high cholesterol. Each endeavor is a bet that futuristic science can turn into money-making medicines. By the end of the year, well have a decent idea of whether its a wise one.

Remember 2015, when the FDA would approve or reject a drug, and people would form an opinion and move on? That all changed the following year when the agency approved eteplirsen, now called Exondys 51, which is a treatment for Duchenne muscular dystrophy from a company called Sarepta Therapeutics (SRPT).

Without relitigating the whole ordeal, its fair to say Sareptas case relied on scant, debatable evidence from a small trial. To some, the FDAs decision to approve eteplirsen anyway was a sign of forward-thinking regulation that put patients first. To others, it was a dereliction of duty that threatened to erode decades of pharmaceutical jurisprudence. And to a great many, it was reason to get on the internet and be churlish, conspiratorial, and even threatening.

On Twitter, the fight over eteplirsen has never really ended, just taken on different forms, like a biotech analog to Gamergate. Earlier this year, the debate over a heart drug made by Amarin (AMRN) quickly metastasized into eteplirsen redux, with name-calling, accusations of bad faith, and armchair psychoanalysis of FDA staff. There were smaller but similar fights over Axovant Sciences, Clovis Oncology (CLVS), and nearly every biotech company with a sizable short interest.

Its at least somewhat understandable why eteplirsen marked such a shift in biotech discourse. Where FDA past decisions seemed to come down from Mount Sinai with little in the way of transparency, the messy eteplirsen process made public internal infighting and clashing personalities at the agency. The FDAs top drug evaluator even considered Sareptas balance sheet while evaluating the drug, a departure from the agencys hands-off approach to the business of biopharma and evidence that approval decisions can be about more than benefits and risks.

Theres no evidence that the FDA was fundamentally changed by a single decision, as organizations that employ 17,000 people rarely are. But that peek behind the curtain was enough to give credence to seemingly any biotech bull case online. Where the FDA once appeared monolithic, now there were heroes and villains within, actors whose imagined biases could support any conspiracy theory. Formerly anonymous public servants became the topic of vicious debate among strangers with alphanumeric Twitter handles and pictures of dogs as online avatars. One even got called a cuck.

With all that as a backdrop, next year, Biogen (BIIB) is going to ask the FDA to approve aducanumab, a treatment for Alzheimers disease. The supporting data are confusing, drawn from a pair of terminated trials with divergent results. The agencys decision will have major implications for the drug industry, the health care system, and the more than 5 million Americans with Alzheimers.

And, on the fractious little planet that is biotech Twitter, aducanumab presents an opportunity to play out the eteplirsen debate on the grandest scale yet, with more kremlinology, more circular logic, and more vitriol. Be nice to one another out there.

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3 trends in biotech to watch in 2020 - STAT