Biopharma tackles COVID-19, HIV and other viruses with gene and cell therapies

When Celularity spun out of Celgene in 2018 with $250 million and a plan to develop cell therapies from placenta to treat cancer, the science was still several years away from translating into marketable products. Then the COVID-19 pandemic exploded, and Celularity’s researchers raced to apply the science behind their cell therapies to fighting the new virus.

What emerged was CYNK-001, an off-the-shelf therapy made from immune cells in placenta called natural killer (NK) cells. It’s similar to the cell therapies Celularity is developing for cancer, explained founder and CEO Robert Hariri, M.D., Ph.D., in an interview.

“We learned that the way natural killer cells identify cancer cells is by recognizing the expression of stress antigens,” which are immune-stimulating molecules on the cells’ surfaces, Hariri said. “Well, it turns out virally infected cells express similar stress antigens.”

A few months of preclinical work was enough to persuade the FDA to allow the company to launch a clinical trial of CYNK-001, and it's now recruiting COVID-19 patients in New Jersey and Washington.

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CYNK-001 is among a rapidly growing collection of gene and cell therapies now in development to treat and prevent a wide range of viruses.

Biopharma companies and academic researchers have created engineered immune cells, CRISPR-edited gene products and more to combat not just COVID-19 but also influenza and HIV, the virus that causes AIDS. Though many challenges have to be overcome before these therapies are ready for widespread use against viruses, early signals suggest they could offer a promising new strategy.

Harnessing immunity from recovered patients

Another company that made a quick pivot to address COVID-19 is AlloVir, which launched back in 2013 with a plan to develop T-cell therapies to treat viruses.

When the pandemic hit, the company was busy with phase 2 trials of Viralym-M, a T-cell treatment for six viruses common in immunocompromised people, including cystitis and cytomegalovirus. Allovir started looking at COVID-19 along with its research partners at Baylor College of Medicine.

AlloVir’s development platform centers on taking T cells from people who've recovered from viral illnesses, separating them from other cells that could spark a rejection response, expanding them and then making them available off-the-shelf to patients fighting those illnesses. The company is applying the same approach to COVID-19, hoping to get a product into clinical trials by the end of the year.

“There’s new evidence every day that COVID patients with acute problems have deficits in their T cells,” said Ann Leen, Ph.D., co-founder and chief scientific officer of AlloVir, in an interview.

“We’ve been looking at the immune response from people who naturally control this virus without needing hospitalization," she said. "We are learning lessons about the important antigens or protein targets within the virus. And these donors—what I call ‘natural controllers’—will also serve as the source of our virus-specific T cells.”

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Gene therapy is also yielding new ways to fight viral illness. Stanford University researchers developed a CRISPR gene editing approach to crippling viruses by destroying nucleotide sequences in their genomes. In June, they reported that the system (called PAC-MAN), could be used to attack the H1N1 flu strain in human lung cells. Now, they’re working on adapting the technology to COVID-19.

And a team led by Harvard University’s Massachusetts General Hospital is working on a COVID-19 vaccine designed to touch off an immune response by delivering fragments of SARS-CoV-2 into the body with an adeno-associated virus (AAV) vector. It’s similar to gene-therapy technology used in FDA-approved products like Novartis’ Zolgensma to treat spinal muscular atrophy. In fact, Novartis agreed in May to manufacture the Mass General vaccine for clinical trials.

“The fact that there’s an established industry out there around AAV made it easy for us to step into the existing [manufacturing] capacity, rather than having to build it,” said Luk Vandenberghe, Ph.D., an associate professor at Harvard Medical School, in an interview. Mass General was also able to speed up preclinical development by teaming with gene-therapy pioneers at the University of Pennsylvania.

Deploying CRISPR against hidden HIV reservoirs

Excision BioTherapeutics is applying both CRISPR and AAV delivery toward solving a different but equally vexing problem in antiviral drug development: HIV. Even though antiretroviral drugs can tamp down the virus to the point where it’s no longer detectable in the blood, it can hide out in “reservoirs” and emerge later.

Excision licensed gene-editing technology developed at Temple University that uses CRISPR to cut out several pieces of the HIV genome. “If you just make a single cut, the virus can mutate around it. We make multiple cuts to deactivate the viral genome,” CEO Daniel Dornbusch said in an interview. A recent trial in nonhuman primates showed the CRISPR version reached every tissue in the body where HIV reservoirs reside, Dornbusch said.

Excision is working on similar treatments for other viruses, including herpes and hepatitis B, and with the proper funding, it could even address COVID-19, he added. But the company’s priority is to gain FDA approval to start human testing of the HIV treatment by the end of this year.

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Sangamo Therapeutics is also working on eliminating HIV reservoirs with gene editing, in collaboration with scientists at Case Western University. Their technique, called zinc finger nuclease gene editing, uses engineered proteins to knock a particular gene—CCR5, which shuttles HIV into host cells—out of T cells. In an ongoing clinical trial, 20 patients are receiving the T-cell therapy and 10 a placebo.

The researchers hope to show that the treatment will boost levels of CD4+ T cells, which work to eliminate HIV reservoirs, said Rafick-Pierre Sékaly, Ph.D., a professor at Case Western, in an interview. “You have to confront the virus with more than one mechanism. Drugs target only one component,” he said. “They don’t rescue the immune response and they don’t restore CD4 numbers. HIV eradication can’t be a single-component issue.”

Hurdles ahead

Developers of gene and cell therapies are facing plenty of challenges, to be sure. They’ll need ample safety trials to demonstrate their products stimulate the immune system without causing unintended side effects, for example. And ultimately, they’ll have to demonstrate the value of choosing these new therapies over older and often less expensive treatments, like antiviral drugs.

In the current moment, they also face a pandemic that's grown increasingly politicized.

Celularity’s Hariri found himself in the crosshairs of critics who thought he was hyping the potential of cell therapy in COVID-19 after he appeared on a podcast in late March with Rudy Giuliani, President Donald Trump’s attorney. Hariri said the attention from a government official shouldn’t lead anyone to assume the biopharmaceutical industry is cutting corners to get COVID-19 remedies on the market.

“It was an informative discussion. It was not about politics whatsoever,” Hariri said.

Hariri hopes the biopharma industry will put politics and rivalries aside and focus instead on working together to solve the logistical challenges of tackling viruses with gene and cell therapies.

“The critical issue in my mind is that for any therapy to impact the force of the pandemic, we have to be ready to have a scalable process that can produce millions of doses," he said. "That’s going to require coordination between many organizations.”