HSPA5

GRP78 is a promising CAR T-cell immunotherapy target for brain and solid tumors. Discover why it's special, including how cancer uses it to trick immune cells. Findings from St. Jude Children's Research Hospital are moving the field of cancer immunotherapy one step closer to treating brain and solid tumors. Scientists at St. Jude validated a cellular immunotherapy target called 78-kDa glucose-regulated protein (GRP78) in proof-of-principle experiments. The group also discovered a resistance mechanism whereby some tumors trick the cancer-killing immune cells into expressing GRP78, thereby turning off the immune cells or causing them to be killed, too. The research, which has implications for developing immunotherapy for the broad range of difficult-to-treat brain and solid tumors expressing GRP78, was published today in Cell Reports Medicine. Reprogramming a patient's immune cells to target cancer has been successful against leukemia but not brain or solid tumors. These reprogrammed cells, called chimeric antigen receptor (CAR) T cells, target a specific protein expressed on cancer cells but not healthy ones. This targeting enables CAR T-cell immunotherapy to kill the tumor while leaving healthy tissues unharmed selectively. One difficulty that has stymied the success of CAR T cells in brain and solid tumors is the challenge of identifying a good target for these cancers. "We found GRP78 is a great CAR T-cell target," said senior co-corresponding author Giedre Krenciute, Ph.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. "We saw high GRP78 expression in a multitude of brain and solid tumor types, including adult glioblastoma, diffuse intrinsic pontine glioma (DIPG), osteosarcoma, triple-negative breast cancer and Ewing sarcoma, but our therapeutic efficacy was variable." The researchers created GRP78-targeted CAR T cells that successfully killed many types of cancers in both cell and mouse models, though with significant variation. The researchers expected that higher levels of GRP78 (more protein to target) would make it easier for the CAR T cells to locate and destroy the cancer; however, that was not the case. The scientists found no relationship between the amount of GRP78 and the ability of the CAR T cells to kill cancer. "We showed the conventional approach of targeting expression doesn't mean an equal response," said co-corresponding author Paulina Velasquez, M.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. "GRP78 seems to be a special target that did not react as we expected, making it a promising but complicated candidate." Tumors trick CAR T cells "We expected two different tumors with the exact same level of antigen [GRP78] expression to be affected by the CAR T-cell therapy in the same way, but they aren't," said first author Jorge Ibanez, Ph.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. "Instead, we found certain tumor cell types were altering T-cell activation and T-cell GRP78 expression." Ibanez found that resistant tumor cell types were altering the CAR T cells. The tumor cells caused the GRP78-targeted CAR T cells to express GRP78 on the CAR T cells' surface. The more GRP78 on the T cells, the less active they became, reducing their cancer-killing activity. In addition, CAR T cells that remained active targeted and killed their counterparts expressing GRP78 on their surface. In effect, the resistant tumors were conning the CAR T cells. These tumors raised the flag of GRP78, saying, "I'm here," and then convinced the approaching T cells to raise their own GRP78 flag. This tricked the CAR T cells into killing each other or giving up, leaving the tumor relatively unscathed. Through these experiments, the St. Jude group unveiled the tricky biology of GRP78. The protein remains a tantalizing target, given its presence on many difficult-to-treat tumor types. Findings show scientists will need to expand their understanding of this newfound interaction with T cells to make viable GRP78-targeted immunotherapies. Still, if they can, these CAR T cells may be broadly applicable across a broad range of tumor cell types. "We always need to find new targets to improve cancer treatment," Krenciute said. "What we found from a biological perspective is that GRP78 has potential but is different from previous cancer-associated molecules. We showed that as scientists develop the next generation of CAR T-cell therapies, we need to recognize that not all targets are equal."

VANCOUVER, BC, June 6, 2023 /PRNewswire/ -- Bold Therapeutics, a clinical-stage biopharmaceutical company developing first-in-class oncology therapeutics, announced positive interim results in advanced gastric and biliary tract cancer at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Bold Therapeutics' BOLD-100 is a first-in-class ruthenium-based small molecule therapeutic that (1) alters the unfolded protein response (UPR) through selective GRP78 inhibition; and (2) induces reactive oxygen species (ROS) which causes DNA damage and cell cycle arrest. Collectively, these effects result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies ranging from traditional chemotherapies to targeted therapies and immuno-oncology agents. Bold Therapeutics' ongoing multinational Phase 1b/2 trial (NCT04421820) evaluates BOLD-100 in combination with FOLFOX (folinic acid / leucovorin, fluorouracil, and oxaliplatin) in patients with advanced gastrointestinal cancers. The trial has enrolled 110 patients with advanced gastrointestinal (biliary tract, colorectal, gastric, and pancreatic) cancers at sites in Canada, the United States, Ireland and South Korea, and the primary endpoints for the trial are progression-free survival (PFS), with overall survival (OS) and overall response rate (ORR) as secondary endpoints. Disease control rate (DCR) was also captured. Data from the full Phase 2 trial, which will include an additional 20 patients with advanced colorectal cancer, should be available in late 2023. Data from 13 patients with advanced gastric cancer and 22 patients with biliary tract cancer was presented in the Gastrointestinal (Gastroesophageal, Pancreatic and Hepatobiliary) Cancer session as Poster 4098: "BOLD-100-001 (TRIO039): A Phase 1b/2a Study of BOLD-100 in Combination with FOLFOX Chemotherapy in Patients with Pre-Treated Advanced Gastric and Biliary Tract Cancer: Efficacy and Safety Analysis." 13 advanced gastric cancer patients (median 4th line) showed a median PFS of 5.5 months, OS of 15.0 months, ORR of 22%, and DCR of 89%, substantially higher than the most comparable benchmark values in a much earlier (median 2nd line) population of a median PFS of 4.6 months, OS of 7.1 months, ORR of 40%, and DCR of 69%. Mature data in an additional 8 advanced gastric cancer patients will be available in late 2023. 22 advanced biliary tract cancer patients (median 3rd line) showed a median PFS of 5.0 months, OS of 7.3 months, ORR of 6%, and DCR of 83%, substantially higher than the most comparable benchmark values in an earlier (true 2nd line) population from the ABC-06 FOLFOX study with a median PFS of 4.0 months, OS of 6.2 months, ORR of 5.0%, and DCR of 33%. Consistent with prior data, BOLD-100 in combination with FOLFOX proved to be exceptionally well-tolerated, with no new safety signals, and with patients remaining on therapy for up to 25 treatment cycles. Treatment-emergent adverse events (TEAEs) were observed in 33 (94%) of patients, with the most common TEAEs being decreased neutrophil count (43%), nausea (29%), and fatigue (20%) – rates comparable to FOLFOX. Previously, interim data in metastatic colorectal cancer presented at AACR 2023 indicated that patients treated with BOLD-100 and FOLFOX showed a median PFS of 4.7 months, OS of 9.8 months, ORR of 13%, and DCR of 87%, substantially higher than standard-of-care data for a similar patient population which showed a median PFS of up to 2.0 months, OS of up to 7.1 months, ORR of up to 1.6%, and DCR of up to 44%. "Our presentation at ASCO marks a critical milestone for BOLD-100, with Bold Therapeutics successfully generating positive proof-of-concept data in three different difficult-to-treat gastrointestinal cancer indications where existing therapies are largely ineffective," stated Jim Pankovich, EVP of Clinical Development. "Importantly for patients, BOLD-100 achieves these improved outcomes safely, even in heavily pre-treated patients." Bold Therapeutics is preparing to initiate a pivotal Phase 3 trial for BOLD-100 in the treatment of advanced colorectal cancer in 2024 and is currently evaluating potentially synergistic development and commercialization partnerships to support these efforts. Concurrently, Bold Therapeutics is exploring additional development indications for BOLD-100 while also advancing its pipeline of other novel metallotherapeutics. For more information or for interest in investing, please visit the Company's website at Contact: E. Russell McAllister, CEO 360208@email4pr.com (604) 262-9899

VANCOUVER, BC, June 1, 2023 /PRNewswire/ -- Bold Therapeutics, a clinical-stage biopharmaceutical company developing first-in-class oncology therapeutics, will be presenting positive interim results in advanced gastric and biliary tract cancer at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting on June 2-6, 2023 in Chicago, Illinois. These results will be presented in the Gastrointestinal (Gastroesophageal, Pancreatic and Hepatobiliary) Cancer session on June 5, 2023 from 8:00AM – 12:00PM CT as Poster 4098: "BOLD-100-001 (TRIO039): A Phase 1b/2a Study of BOLD-100 in Combination with FOLFOX Chemotherapy in Patients with Pre-Treated Advanced Gastric and Biliary Tract Cancer: Efficacy and Safety Analysis." This poster includes progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) data in gastric and biliary tract cancer and expands on data in metastatic colorectal cancer presented earlier this year at the American Association for Cancer Research (AACR) 2023 conference. With compelling interim Phase 2 data in three different difficult-to-treat oncology indications (colorectal, gastric, and biliary tract), BOLD-100's disruptive therapeutic potential is becoming increasingly evident. BOLD-100 is currently being studied in a global Phase 1b/2 trial for the treatment of advanced gastrointestinal cancers, with 110 patients successfully treated to date. Phase 1b trial results, presented at ASCO 2022, demonstrated that BOLD-100 in combination with FOLFOX was generally safe and well-tolerated. Interim Phase 2 data in metastatic colorectal cancer presented at AACR 2023 indicated that patients treated with BOLD-100 and FOLFOX showed a median PFS of 4.7 months, OS of 9.8 months, ORR of 13%, and DCR of 87%, substantially higher than standard-of-care data (Bayer's Stivarga® and Taiho's Lonsurf®) for a similar patient population which showed a median PFS of up to 2.0 months, OS of up to 7.1 months, ORR of up to 1.6%, and DCR of up to 44%. In addition, BOLD-100 in combination with FOLFOX proved to be exceptionally well-tolerated, with no new safety signals, and with patients remaining on therapy for up to 15 treatment cycles. Data from the full Phase 2 trial, which will include an additional 20 patients with advanced colorectal cancer, should be available in late 2023. Bold Therapeutics' BOLD-100 is a first-in-class ruthenium-based small molecule therapeutic that (1) alters the unfolded protein response (UPR) through selective GRP78 inhibition; and (2) induces reactive oxygen species (ROS) which causes DNA damage and cell cycle arrest. Collectively, these effects result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies ranging from traditional chemotherapies to targeted therapies and immuno-oncology agents. BOLD-100 was previously granted orphan drug designations (ODDs) in gastric and pancreatic cancer and expects additional ODDs and/or breakthrough therapy designations (BTDs) expected in 2023 and 2024. Bold Therapeutics is preparing to initiate a pivotal Phase 3 trial for BOLD-100 in the treatment of advanced colorectal cancer in 2024 and is currently evaluating potentially synergistic development and commercialization partnerships to support these efforts. Concurrently, Bold Therapeutics is exploring additional development indications for BOLD-100 while also advancing its pipeline of other novel metallotherapeutics. Additional information on ASCO For more information, please visit the Company's website at Contact: E. Russell McAllister, CEO 359904@email4pr.com (604) 262-9899