Incorporating biomaterials into the design of CAR T cells may yield new, improved versions of this immunotherapy. Two preclinical studies indicate the potential of using biodegradable nanoparticles to program circulating T cells into CAR T cells in situ, and delivering these therapeutic cells directly to solid tumors via small dissolvable sponges.
Even as companies race to have the first FDA-approved chimeric antigen receptor (CAR) T-cell therapy, innovative iterations are emerging at the bench. A promising approach may be to incorporate biomaterials into the design of this immunotherapy, as demonstrated by two preclinical studies from Fred Hutchinson Cancer Research Center in Seattle, WA.
Immunobioengineering is a young field, says senior author Matthias Stephan, MD, PhD, but it could make CAR T-cell therapy more widely applicable and “not such a big deal,” referring to the elaborate protocols currently required to manufacture these cells ex vivo.
In one study, Stephan and his team evaluated polymer-based nanoparticles that bind CD3 on T cells and deliver their cargo—a CAR gene for CD19—to be integrated into the cell nuclei (Nat Nanotech 2017 April 17 [Epub ahead of print]). When these biodegradable nanoparticles were injected into mice with acute lymphoblastic leukemia (ALL), circulating T cells were successfully converted, in situ, into CD19-targeting CAR T cells within 24 hours.
“We turned naïve T cells into serial killers that were already at their job site and could immediately eliminate tumors,” Stephan explains. The newly minted therapeutic cells' huge proliferative capacity prompted their rapid self-expansion, he adds, so “although the [CAR] gene transfer process was fairly inefficient, we only needed an initial spark to start the fire.”
These in situ programmed CAR T cells eradicated ALL in seven of 10 mice; the rest experienced substantial disease regression and a median 58-day improvement in survival. The efficacy data were not significantly different from those for a control group of mice given conventionally generated CAR T cells, Stephan notes.
This “very novel approach may shake up the gene and cell therapy fields to think in new, fresh ways,” observes Crystal Mackall, MD, of Stanford University in Palo Alto, CA. “The results are preliminary but highly impressive, illustrating the untapped potential of marrying nanomedicine with genetic engineering.”
“Our goal is for CAR T-cell therapy to outcompete chemotherapy as a first-line treatment [for leukemia/lymphoma], because it can be prescribed and administered just as easily,” Stephan says.
Meanwhile, to better apply CAR T-cell therapy to solid tumors, which are highly heterogeneous compared with hematologic malignancies, the team developed what Stephan describes as “a simple tool for surgeons” (J Clin Invest 2017;127:2176–91). It involves implanting alginate-based sponges within the cavity of a resected tumor, or directly on the surface of otherwise inoperable tumors. These dissolvable quarter-sized sponges serve as scaffolds that can be loaded with CAR T cells (conventionally manufactured ex vivo) plus an optimal mix of growth factors to stimulate proliferation.
Importantly, expansion of CAR T cells to destroy tumor cells expressing a given antigen—in this case, NKG2D—is “just the first wave,” Stephan says. The scaffold is designed to simultaneously deliver a STING agonist that primes a second, broader immune response by recruiting and stimulating dendritic cells capable of recognizing multiple other tumor antigens. STING agonists are “very potent vaccine adjuvants and too toxic to be given intravenously,” he adds, but these small sponges can safely deliver high local concentrations that synergize with CAR T cells in antitumor activity.
In mouse models of pancreatic cancer and melanoma, the researchers observed complete tumor eradication, or appreciable regression and prolonged survival, with this approach. Scaffold placement may not require invasive surgery, Stephan adds; the team has found that it can be done laparoscopically in nonhuman primate models.
Stephan's research “is consistently among the most innovative at the interface of adoptive cell therapy and biomaterials,” says Michael Goldberg, PhD, of Dana-Farber Cancer Institute in Boston, MA. “This platform is worthy of consideration for clinical translation—the data confirm that the efficacy of CAR T-cell therapy is vastly augmented if these cells are released in the presence of factors supporting both innate and adaptive immunity.”
“We need industry partners who are adventurous enough to combine bioengineering with immunotherapy,” Stephan says. Given the present focus among major CAR T-cell therapy players on crossing the FDA-approval finish line, he thinks smaller biotechs may be better positioned to advance both nanoparticle and scaffold strategies in the clinic. –Alissa Poh
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