Bellicum Pharmaceuticals Inc., whose name loosely translates from Latin as "call to war," is developing technology that seeks out and eliminates the donor T cells that cause graft-vs.-host disease (GVHD), an often-fatal complication of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute leukemia.
The company's so-called CaspaCIDe technology consists of a drug-inducible "suicide" gene (iCasp9) introduced into therapeutic cells that are subsequently given to patients in combination with a drug (AP1903) that physicians administer if the cells cause unacceptable toxicity, triggering the suicide gene and leading to their rapid self-elimination.
Founded in 2004 by Baylor University researchers David Spencer and Kevin Slawin, the Houston-based company's technology is based on chemical induction of dimerization (CID). The drug-based "remote control" process enables a physician to control the fate of a cell inside the patient, according to Thomas Farrell, Bellicum's CEO.
The CaspaCIDe application is the cell therapy "safety switch," Farrell explained, permitting the rapid elimination of cells in the event of toxicity.
CaspaCIDe donor lymphocyte infusion (DLI) is administered following HSCT, enabling physicians to activate the switch, if needed, to resolve GVHD.
A study published Nov. 3, 2011, in The New England Journal of Medicine reported rapid and complete reversal of GVHD using CaspaCIDe to eliminate the donor T cells causing GVHD in five patients with acute leukemia, including some who had previously relapsed.
The patients underwent HSCT from high GVHD risk, partially HLA-mismatched, haploidentical donors. In all five transplants, the CaspaCIDe suicide gene was inserted into the donor T cells, which were then infused into the patients. Weeks later, the gene-modified donor cells were detected in the peripheral blood of all patients, functioning as expected and expanding in number over time.
Four of the patients went on to develop GVHD and were treated with a single dose of AP1903. Within 30 minutes, 90 percent of the gene-modified T cells were eliminated, and the symptoms of GVHD disappeared in the treated patients within 24 to 48 hours, without the need for steroids. The surviving T cells re-expanded and continued to help control infections, without recurrence of GVHD, indicating that CaspaCIDe preferentially eliminated those T cells that cause GVHD.
The study provided direct proof in principle of the core CID technology, Farrell told BioWorld Today.
"This particular application is controlling apoptosis within the cell, allowing us to trigger cell death, but the same technology can be applied to more or less any signaling pathway inside the cell," he said. "Since all of our programs are based on that technology, to a certain extent it's a de-risking result."
The company also is using the CID technology to develop therapeutic vaccines designed to kill targeted cells by inducing a fully activated, antigen-specific T-cell immune response. Lead product BPX-101, an autologous DeCIDe vaccine, is in Phase I/II studies for patients with metastatic castrate-resistant prostate cancer (mCRPC).
The CID technology was co-invented by Spencer while at Stanford University, then licensed and further developed by Ariad Gene Therapeutics, which was merged in 2008 into Ariad Pharmaceuticals Inc., of Cambridge, Mass. In 2006, Bellicum signed a nonexclusive, royalty-bearing licensing agreement with Ariad for the cell-signaling regulation technology, with Ariad taking an equity stake in the small biotech.
Earlier this year, Ariad and Bellicum expanded their agreement, with Bellicum receiving exclusive licenses to develop products to treat complications of cell transplantation such as GVHD as well as cancer immunotherapies using AO1903, a small-molecule dimerizer.
Slawin, a urologist and director of the Vanguard Urologic Institute and the Texas Prostate Center, and Spencer, an immunologist, have aimed "to improve on the very limited, or nonexistent, activity seen with Provenge while keeping the very attractive safety profile," said Farrell, who joined Bellicum in 2006 and until recently was the only full-time employee.
Ironically, Dendreon Corp., of Seattle, which developed Provenge (sipuleucel-T), saw its stock fall 37.4 percent the same day the Bellicum technology was reported in the NEJM, largely based on missed expectations from the prostate cancer vaccine and fears that a newcomer could eclipse its modest success. (See BioWorld Today, Nov. 4, 2011.)
For the past five years, Bellicum has operated virtually while seeking to move candidates into the clinic so that outsiders "would take us seriously," Farrell said. In 2008, the FDA approved the company's investigational new drug application for BPX-101 in mCRPC, and the company initiated its Phase I/II trial of the compound the following year. Data reported earlier this year at the annual meeting of the American Society of Clinical Oncology in Chicago found that the combination of BPX-101 and AP1903 was safe and well tolerated at doses of up to 25 million cells and 0.4 mg/kg respectively, and elicited immunological responses, including DTH reactions and serum cytokine "spikes" in most of the 12 patients evaluated.
Bellicum also has met with the FDA to discuss launching Phase II trials of the CaspaCIDe technology in 2012.
Now with seven employees and plans to expand to a dozen by early next year, the company has raised more than $17 million, including $9.8 million from angel investors and $7.1 million in grant funding. Bellicum is set to close a Series B that will finance the next round of clinical trials, scheduled to conclude in 2013.
The company has received some outside interest, primarily on the vaccine side of its portfolio, but "it's a little early to be in the sweet spot for partnering," Farrell observed.
The vaccine platform is moving in the direction of an off-the-shelf product, "which may open more attractive partnering opportunities," he said. Bellicum also will consider the prospect of building the company internally, since each large transplantation center offers a potentially captive business stream.