Special Report: Biopharma nurtures the next generation of immuno-oncology targets

lymphocytes
Finding new ways to trick the immune system into attacking cancer is a hot pursuit in oncology R&D. (La Jolla Institute)

On Sept. 1, Gilead struck a development deal for an immuno-oncology asset—the value of which spoke volumes about the industry’s enthusiasm for emerging immune targets for treating cancer. Gilead paid $85 million upfront, invested $35 million in equity and vowed up to $685 million in development milestone payments to Jounce Therapeutics to license its preclinical asset JTX-1811.

JTX-1811 targets a receptor on immunosuppressive tumor-infiltrating T regulatory (TITR) cells, which normally help tumors evade detection by the immune system. The drug is designed to bind to the receptor on the cells, which labels them for depletion. The deal came just months after Gilead struck a $2 billion deal with Arcus to develop a range of immuno-oncology treatments.

RELATED: Gilead pens $2B Arcus pact for immuno-oncology targets of the past and future

The first wave of immuno-oncology drugs were targeted at immune checkpoints and produced blockbusters like Merck’s PD-1 inhibitor Keytruda. The next wave includes second-generation checkpoint inhibitors along with drugs that interact with a wide range of emerging immune targets.

“This is the future—understanding what’s happening in the tumor microenvironment,” said Jill O’Donnell-Tormey, CEO and director of scientific affairs at the Cancer Research Institute, in an interview. “Once we understand mechanistically how [immune targets] interact with cancer-killing T cells, once we really understand that tumor microenvironment, we’ll be able to modulate it.”

Investing in new I-O targets

One emerging immune target that has caught the attention of the immuno-oncology community is TIGIT, which is expressed on lymphocytes and has been shown to interact with CD155 on tumor cells to suppress cancer-fighting immune cells. In 2018, Merck reported that combining its investigational TIGIT-targeted drug with Keytruda in advanced solid tumors stabilized disease in 40% of patients in an ongoing phase 1 trial. Merck is now recruiting patients for a phase 2 trial of the combo in non-small cell lung cancer (NSCLC).

Roche is following close behind with its TIGIT combo strategy. In May, at the virtual annual meeting of the American Society for Clinical Oncology, Roche’s Genentech unit reported that its anti-TIGIT antibody candidate combined with its PD-L1 blocker Tecentriq caused tumors to shrink in 31% of patients with NSCLC, handily beating Tecentriq alone.

Gilead’s deal with Arcus also includes an anti-TIGIT candidate, which the company recently moved into phase 2 testing in NSCLC. Arcus is combining the drug with its own PD-1 blocker zimberelimab.

Another immune target, CD47, has long been of interest because of mounting evidence that tumors use the protein to evade immune attacks. Problem is, blocking CD47 can cause dangerous hematological side effects. Now, several companies are saying they’ve hit upon the ideal risk-benefit profile with their anti-CD47 drugs, including ALX Oncology, which raised $105 million in a February series C financing. It’s now moving its CD47-targeted drug ALX148 into phase 2 trials, backed by a $162 million initial public offering the company pulled off in July.

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In March, Gilead made one of the biggest bets on CD47 yet, laying out $4.9 billion to buy Forty Seven and its mid-phase candidate magrolimab. Forty Seven turned heads back in 2018 with trial data showing that a combination of the drug with Roche’s Rituxan shrank the cancers of half of patients with non-Hodgkin lymphoma who had failed or relapsed after two previous treatments.

Now, AbbVie has jumped into the race to develop an anti-CD47 drug with a $2 billion collaboration with I-Mab to develop lemzoparlimab. The deal came after Forty Seven released data from a clinical trial showing that when the drug was combined with Celgene’s Vidaza, more than 50% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia had a complete response. Updated data released in May showed that the positive responses grew over time, with 56% of MDS patients showing a complete response at six months.

Meanwhile, new immune targets are emerging. They include BTN3A, which is over-expressed in many solid tumors and blood cancers and has been shown to activate certain anti-tumor T cells in response to specific stress signals. In December 2019, a leading player in the BTN3A field, France-based ImCheck, scooped up $53 million in a series B funding round that was co-led by Pfizer Ventures, and then the company added another $7 million to the round this month. ImCheck has now started clinical trials of a BTN3A-targeted drug.

Improving on the old guard

Much of the development work in immuno-oncology is focused on improving upon the targeting of well-established immune checkpoints like PD-1.  Startup Shattuck Labs, for example, is developing molecules that not only remove the brake on the immune system, but also prompt T cells to attack cancer cells. Takeda has partnered on the development of Shattuck’s anti-PD-1 drug, and, in June, the company raised $118 million in a series B round to advance its pipeline.

The market for drugs that block the checkpoint CTLA-4 is currently dominated by Bristol Myers Squibb's Yervoy, which brought in $1.5 billion in sales in 2019. Now other companies are hoping to contribute new choices to the anti-CTLA market, including Agenus and MacroGenics, which are in early-stage testing of their candidates. MacroGenics is testing a bispecific drug that hits both PD-1 and CTLA-4. The candidate came from its DART drug development platform, which has garnered investments from the likes of Roche.

RELATED: Takeda-partnered Shattuck nabs mighty $118M funding round for immunotherapy, autoimmune work

Some efforts to improve on known checkpoints have hit hurdles, though. Novartis is testing its anti-PD-1 candidate spartalizumab in combination with Tafinlar/Mekinist in the first-line treatment of patients with melanoma who test positive for the BRAF V600 mutation and who are not eligible for surgery. Tafinlar and Mekinist are tyrosine kinase inhibitors that slow the growth of BRAF-mutated melanoma cells.

In August, Novartis revealed that the combo did not meet its primary endpoint in a trial involving more than 500 advanced melanoma patients. Novartis has several other trials of spartalizumab combinations ongoing in multiple tumor types, including glioblastoma, lung cancer and esophageal cancer.

Will such setbacks dampen immuno-oncology R&D? Said O’Donnell-Tormey: “I worry people are going to say immunotherapy is a flash in the pan, but I don’t believe it is. The immune system is complicated—it’s going to take these types of errors to figure it out. And there are still over 550 immuno-oncology targets being pursued.”

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