The natural immune system has two lines of defense that complement each other. In response to an infection, a rapid but fairly unspecific and short-lived response by the innate immune system is followed by the precisely targeted attack of the B and T cells of the adaptive immune system, followed by immune memory that can last a lifetime.  

Clinical oncology has so far looked to the adaptive immune system for weapons against cancer. In particular, the profound advances seen in tumor immunotherapy are centered around T cells. “As a field, we have been extremely T-cell-centric,” said Justin Gainor, director of targeted immunotherapy at Massachusetts General Hospital’s Henri and Belinda Termeer Center for Targeted Therapies. 

Gainor was speaking at an investor event put on by ALX Oncology during the recent American Society of Hematology (ASH) annual meeting in Orlando, Fla. At the meeting, ALX presented new data for its CD47 blocker, ALX-148, one of several approaches whose goal is to harness the innate immune system in the antitumor fight.   

Forty Seven Inc.’s data may have been early stage – at ASH, the company reported results from a phase Ib trial of its CD47 blocker, magrolimab. But the company made headlines and stock gains off the data. The stock (NASDAQ:FTSV), which was trading in the teens for much of the year, has been in the mid-30s range since the company reported a combination treatment of magrolimab and azacitidine netted an overall response rate (ORR) of 92% in 24 patients with untreated myelodysplastic syndrome (MDS), and a 64% ORR in 22 patients with untreated acute myeloid leukemia (AML). 

CD47 is a surface molecule that is expressed by many cells, and overexpressed by tumor cells, to avoid becoming the target of macrophages, the innate immune cells that engulf and digest foreign invaders and tumor cells as well as cellular debris and just about anything that they come across that is not expressing CD47. Known as the “don’t eat me” signal, CD47 is recognized by the signal regulatory protein α (SIRPα), which is expressed on macrophages. 

There are several cells that express the CD47 receptor SIRPα. But to a first approximation, the CD47/SIRPα axis is the innate immune equivalent of the PD-1/PD-L1 axis that is now the target of half a dozen checkpoint blockers.  

At the CD47/SIRPα summit, held in Boston in the Spring of 2019, Shattuck Labs Inc.’s chief scientific officer, Taylor Schreiber, described it as “clinically derisked to a level that has not been seen since the early PD-1/PD-L1 days.” 

That is not to say the target is low-risk. Also at ASH, a Yale-led team reported that Celgene Inc.’s CD47 targeting CC-90002 flopped as a monotherapy in high-risk MDS and relapsed/refractory AML, though the company is exploring combination treatments in non-Hodgkin lymphoma (NHL). 

ALX Oncology Inc. reported phase I NHL results at ASH with its CD47-targeting ALX-148 in combination with Rituxan (rituximab, Biogen Inc.). The details of ALX-148 prevent it from causing the dose-dependent cytopenias that are seen with other CD47-targeting drugs, and in the trial presented at ASH, a maximum tolerated dose was not reached, and at the 10-mg/kg dose, 21 patients with relapsed or refractory NHL had an ORR of 43%. 

The company is also testing ALX-148 in solid tumors, including head and neck cancer and gastric cancer, in both 10- and 15-mg/kg weekly doses. 

Killer CARs 

At ASH, companies including Celyad Therapeutics Inc. and Fate Therapeutics Inc. reported progress in applying the CAR T concept to innate immune cells as well. 

Both companies are attempting to use natural killer (NK) cells as CAR T cells, though they are approaching the problem from different angles. 

NK cells, Celyad’s vice president of research & development, David Gilham, told BioWorld, recognize not just one target but eight different surface proteins that are indicators of the cellular stress response. In principle, he added, “tumors are stressed places,” providing a rich source of targets for NK cells, though as with T cells, tumor cells evolve ways to evade NK cells. 

For cell therapy, another issue is that NK cells “are quite hard to grow and have quite a short life,” he said. 

Celyad’s solution has been to insert the NK receptor NKG2D as a chimeric antigen receptor (CAR) into T cells. “It’s the best of both worlds. It’s the ability to have the innate surveillance” as well as the adaptive immune system’s capacity for proliferation, infiltration and immune memory, Celyad CEO Filippo Petti told the audience during an ASH investor event. 

At the meeting, Celyad researchers presented data on the THINK and DEPLETHINK trials, which are testing CYAD-01 in autologous transplants where the patient’s T cells have been engineered with the NKG2D receptor. In those trials, Gilham said, the safety profile has been “very good” – not a given, since CAR cells can be extremely toxic, and the targets of the NKG2D receptor are not unique to tumor cells. 

The trial also yielded some clinical responses, and the company is working to understand which patients are most likely to respond to treatment.  

So far, it appears that responses are related to patient genotype rather than any characteristics of the transplanted cells themselves, which may be due to the fact that AML is something of a catch-all phrase.  

“It’s probably used to cover a few hundred diseases,” Gilham said. “We have to be a bit clever about how we understand the disease.” 

Celyad is also testing both autologous and allogeneic CYAD-01 in phase I trials for patients with metastatic colorectal cancer, and is developing second-generation cells.  

Fate Therapeutics Inc. has a different solution to the challenges of CAR NK cells.  

Fate has used induced pluripotent stem cells (iPSCs) to create master cell banks with uniform cell quality. The company’s induced NK cell-based FT-500 was “the first iPSC-derived product cleared for clinical trials in the U.S.,” Fate’s chief development officer, Bahram “Bob” Valamehr, told reporters at the meeting. It is in phase I trials for the treatment of advanced solid tumors. 

Using master cell lines potentially provides a more uniform therapy than autologous approaches, where, quite apart from the time and expense, “not every cell can be engineered, and not every engineered cell is pristine,” Valamehr said.  

At ASH, the company presented preclinical data, and during the meeting, it released case reports of the first two patients treated with FT-516, one of whom was an AML patient who showed “no morphologic evidence of leukemia, chimerism of FT-516 in the bone marrow, and hematopoietic recovery, including complete neutrophil recovery without growth factor support” after three doses of FT-516 plus IL-2.  

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