Academics and industry folks from around the cancer world convened in sunny San Diego Nov. 1-5 at the Society for Immunotherapy of Cancer’s annual conference. Here are a few preclinical highlights.
BCMs add bite to BiTEs
Be Biopharma’s engineered B cell medicines (BCMs) may improve the pharmacokinetics of bispecific T cell engagers, also known as BiTEs. On Nov. 4, Be Bio Director of Oncology Research Sean Arlauckas, Ph.D., presented the results of a proof-of-concept study showing that BCMs producing a biosimilar of blinatumomab—Amgen’s Blincyto—can secrete the drug at levels that meet and even exceed therapeutic concentrations. The study was performed in collaboration with researchers at Seattle Childrens Research Institute.
A quick note about B cells and BCMs for context: B cells are immune cells that create antibodies to pathogens they encounter. When they’re activated by a foreign antigen, B cells present the antigen to T cells then divide into what are known as plasma cells, which secrete the antibodies at a rapid, steady rate of around 2000 molecules per second. Be Bio harnesses these characteristics of B cells to engineer BCMs that can be programmed to secrete therapeutic proteins at a controlled pace at a specific site in the body.
On its own, blinatumomab requires 28 days of continuous infusion, which can’t be interrupted for more than four hours at a time. To make the therapy more efficient, researchers at Be Bio wanted to use their BCM tech to secrete a blinatumomab biosimilar at a constant rate for the full treatment period, negating the need for external infusions.
After a couple rounds of optimization, the researchers cracked the code—at least in mice. In a 17-day study using a mouse model developed with patient-derived acute lymphoblastic leukemia cells, they found that a single dose of the BCM therapy sustained plasma levels of the BiTE at the same or higher concentrations than when clinically-relevant doses of the drug were given via infusion. The therapy also reduced cancer cell growth, even though the type of ALL cells in the model were less responsive to treatment.
Good CAR-M-a
Can CAR-Ms pick up where CAR-Ts drop off? Carisma Therapeutics hopes so. Research presented Nov. 3 showed that a therapy pairing the company’s in vivo chimeric antigen receptor macrophage platform with an mRNA and lipid nanoparticle delivery system—the fruits of a collaboration with Moderna—reduced tumor growth and improved survival in mice with solid tumors.
“CAR-T has been revolutionary for blood cancer, but we see a clear trend where most patients with blood tumors respond and some patients with solid tumors don’t,” Bindu Varghese, Ph.D., who leads the in vivo CAR-M program at Carisma, said during her presentation.
In short, the CAR-M-mRNA platform works like this: lipid nanoparticles containing mRNA with the code for a chimeric antigen receptor programmed against a tumor-specific marker are administered via IV. The particles transfect a patient’s myeloid cells—which include monocytes, macrophages, and dendritic cells—and express the CAR, which redirects the cells to target the patient’s cancer. This not only halts the growth of existing tumors but also has the potential to program an adaptive immune response that recognizes metastases, warding them off before they have a chance to take hold.
The strategy seems to work in mouse models, Carisma’s SITC data showed. First, in mice with HER2-positive tumors, CAR-M administered as a cell therapy shrank tumors, remodeled the tumor microenvironment and activated T cells to join in on the anti-tumor attack. When the researchers modeled recurrence by giving the same group of mice a second round of tumor cells, this time HER2-negative, the treated animals mounted an immune response against them before they could grow.
The researchers at Carisma, in collaboration with Moderna, went on to recreate this principle using an off-the-shelf mRNA-lipid nanoparticle approach—in vivo CAR-M—rather than a cell therapy that is prepared outside of the body. The SITC data showed that the approach worked both when the researchers injected the nanoparticles directly into the mice’s tumors and when it was administered systemically via intravenous injection. In all cases, the therapy was well-tolerated in the mice.
Carisma is currently testing its first CAR-M cell therapy, CT-0508, in early-stage clinical trials, both as a monotherapy and in combination with Keytruda. The company partnered with Moderna to develop up to 12 in vivo CAR-M therapies based on the mRNA/lipid nanoparticle platform disclosed at SITC. Meanwhile, the company is also working on upgrades to its CAR-M tech, as it demonstrated in a pair of posters at the conference. One showed that CAR-Ms with custom intronic short hairpin RNA silencing SIRPa are effective against solid tumors in mice, while a second showed that a platform called engineered microenvironment converters can make tumors more responsive to checkpoint blockade by reversing immunosuppressive signals.
CAR in a SNAP
CAR-T therapies built with Coeptis Therapeutics’ universal SNAP-CAR platform beat back cancer in three different mouse models, including one of solid cancer. The new data was shared in a poster session Nov. 3 by researchers from the University of Pittsburgh, from which the tech was licensed.
The SNAP-CAR platform is designed to overcome some of the limitations of CAR-T therapy, like toxicity and relapse and poor efficacy against solid tumors. Where CAR-T cells are designed to target just one antigen at a time, SNAP-CAR cells can be administered alongside multiple different antibodies that bind to various antigens on tumor cells at once, making it less likely that the tumor will develop resistance to treatment. And oncologists have the ability to control the dose of each antibody given, reducing the risk of side effects and, potentially, boosting the immune response in patients who need additional doses, according to Coeptis.
“The way we see this being a little bit different from some of the other parts of the market is that it’s really all about the multi-targeting because you can use that one [immune cell type] to target different antigens on the same tumor,” Dan Yerace, co-founder and vice president of operations at Coeptis, told FBR in an interview. And while bispecifics also target multiple antigens at the same time, they hit tumors with a “big punch all at once,” he said—a recipe for serious side effects.
“What we think we can do differently is instead of dosing all of these at the same time, if you could perhaps have one antibody first, then layer them in and tune the dosage differently, you may have a better result,” Yerace explained.
The findings presented at SITC included results from studies on cell lines and three different mouse models. In the cells, SNAP-CAR-Ts targeting HER2, EGFR and CD20 cell lines killed cancer cells and increased inflammatory molecule production. In a mouse model of HER2-positive leukemia, the SNAP-CAR-Ts killed off cancer cells to the point that cancer cells were undetectable in most of the tumors. In a second leukemia model, SNAP-CAR-Ts targeting CD20 slowed cancer growth.
In a model of ovarian cancer, the researchers showed that using two different kinds of HER2 adapters that bind to different sites on the HER2 antigen reduced tumors to a greater degree than either with just one adapter or with SNAP-CAR-T cells alone, early validation of a strategy where a single antigen is targeted from multiple angles.
Coeptis is optimizing the SNAP-CAR to work with other immune cells beyond T cells. It’s already designed to work with natural killer cells, and the company hopes to add others to the list. In the meantime, they’ll continue moving the SNAP-CAR-T therapy towards the clinic, looking for partnerships and new targets along the way, Yearce said.
For now, the data is another step on a path that leads to a future where off-the-shelf, plug-and-play cancer treatments are readily available to every patient, Coeptis CEO Dave Mehalick told FBR.
“Imagine the day when we have frozen bags of cells that can be administered to patients and a catalog of antibodies that can attack not only different cancers but also different targets on the cancers,” he said. “The potential of this technology is really dramatic.”