Dragonfly Therapeutics, Inc.

Pictured: NK cells attacking a cancer cell/ selvanegra for iStock When the first CAR T cell therapy was approved by the FDA in 2017, it was heralded as a breakthrough in cancer treatment. The approach allowed for a targeted attack on cancer cells using a patient’s own immune cells, as compared with the broad-strokes assault levied by traditional treatments such as chemotherapy and radiation. While a total of six CAR-Ts have been approved to date, the approach works only for a subset of patients, has shown promise mainly for blood cancers and has notable side effects. To overcome these shortcomings, many researchers and biotech companies have turned their attention to natural killer (NK) cells, which are a part of the innate immune response—the body’s first line of defense against any infection. Historically, NK cells have been notoriously difficult to culture, leading them to be overlooked, said Alicja Copik, associate professor of medicine and core scientist at the University of Central Florida. “Better understanding of how to grow [NK cells] in the laboratory has led to an immense research interest in these cells,” she told BioSpace. “A decade ago, just one company was looking at NK cells. Now, several groups are exploring different ways to use them as cell therapies.” Overcoming CAR-T’s Challenges CAR-T therapies involve reengineering T cells, typically derived from the patient. Once isolated, these cells are genetically modified to express chimeric antigen receptors (CARs) on their surface, arming them to better recognize and attack cancer cells. However, CAR-Ts have been shown to cause several side effects, including cytokine release syndrome, neurotoxicity and blood disorders such as anemia and thrombocytopenia. In terms of allogeneic CAR-Ts, where donor T cells are used, there is the risk of graft-versus-host disease, a strong immune reaction that leads to a rejection of the transplanted cells. “T cells with CARs can go crazy and grow uncontrollably, which leads to some of the major side effects,” said Sumiti Jain, chief scientific officer of ImmuneBridge, a San Francisco–based biotech startup that raised $12 million in seed funding in 2023 to develop NK cells from the umbilical cord. NK cell–based therapies do not cause cytokine release syndrome and neurotoxicity because “they don’t grow as robustly,” Jain said. CAR-Ts have also been associated with secondary malignancies such as leukemias, skin cancers and T cell non-Hodgkin lymphomas. Noting this potential side effect, the FDA recently announced that it will require an update to the boxed warnings of CAR T cell therapies, alerting patients and prescribers to a heightened risk of secondary T cell malignancies. Furthermore, David Shook, chief medical officer of Nkarta, which is developing allogeneic CAR-NK cells, told BioSpace that CAR T cell therapies, despite their benefits, have remained largely inaccessible to patients due partly to a “cumbersome” manufacturing process. The process of isolating and engineering a patient’s T cells takes over two weeks before the cells can be infused back into the patient. “There are patients who are eligible for CAR-Ts and are on the waitlist but are not able to access them because of manufacturing constraints,” Shook said. Advantages of NK Cell Therapy Ann Cheung, chief scientific officer and head of R&D at Dragonfly Therapeutics, which is developing NK cell–stimulating antibodies, noted that, unlike CAR-T therapies, NK cell therapies do not require patients to undergo lymphodepletion chemotherapy with toxic agents such as fludarabine and cyclophosphamide. “Not every patient is eligible for these chemotherapies,” she told BioSpace, because of other immune conditions or a susceptibility to infections. “In that sense, the safety pro NK cell therapies is much better.” Moreover, she said, NK cells work by recognizing multiple antigens, making them strong contenders to destroy cancer cells. NK cell therapies have also shown promise for treating solid cancers, an area where CAR-Ts have largely failed to show benefits, Jain said. “CAR-Ts are amazing for blood cancers, but put them in solid tumors, and they seem to freeze.” NK cells seem to have the ability to migrate into solid tumors better than CAR-Ts, she explained. These characteristics have inspired several biotech and research groups to explore the potential of turning NK cells into therapies. Nkarta is developing CAR-NK cells from a donor-derived pool of NK cells. But after seeing initial success with one candidate, NKX101, an interim evaluation of Phase I data in 14 acute myeloid leukemia patients showed a “meaningfully lower” response rate than in the first six reported patients, causing the company to deprioritize the program. Other companies are moving forward with CAR NK cell therapy candidates. Fate is in Phase I trials with FT522 for B cell lymphoma, and Century has a CD19-targeting therapy, CNTY-101, in Phase I for B cell malignancies. And while some are focused on genetically modifying NK cells to enhance their cancer-fighting abilities, others are harnessing the inherent qualities of NK cells. For example, San Diego–based Artiva Biotherapeutics, in partnership with Merck, is developing a non–genetically modified NK cell therapy that enhances antibody responses to specific cancers and autoimmune diseases. Meanwhile, NKGen Biotech just released interim Phase I data for its allogeneic non–genetically modified NK cell therapy, SNK02, showing that it was well tolerated—all patients completed the eight treatment cycles—and showed signs of clinical activity against pretreated solid tumors. And ImmuneBridge wants to harness the pool of NK cells from hematopoietic stem cells derived from umbilical cords, which Jain said are most likely to show anti-tumor activities against specific cancers. The Road Ahead Despite recent advancements, experts suggest the road ahead for upscaling NK cell therapies may not be straightforward. “NK cells don’t live for very long,” Shook said, so patients may require a high dose and multiple rounds of injections. Jain added that differentiating NK cells derived from donors can exhaust the cells and mellow their potential to be effective cancer killers. “We need durable cell NK therapies,” she said. According to a study of clinical trial data recently published in Nature, the clinical benefits from NK cell–based therapies often lasted only a few months before relapse, likely due to resistance or low NK cell persistence. “NK cell persistence typically ranges from a few days to 4 months, with an average of 7 days,” the authors noted, adding that cryopreservation of NK cells further impacts their ability to grow. While there are currently no FDA-approved NK cell therapies for cancer, Copik is hopeful that some of these therapies will make it to market. “More studies are showing us that the NK cell therapies are effective and have better safety profiles compared to CAR-Ts,” she said. Jain holds a similar view. “Patients are battling every day. Having a new therapy that is readily accessible will be a huge advancement.” Aayushi Pratap is a New York-based health and science journalist and an alum of Columbia Journalism School. Reach her on LinkedIn.

DF9001 is currently being evaluated as a monotherapy for the treatment of Non-Small Cell Lung Cancer, Renal Cell Carcinoma and Head and Neck Squamous Cell Carcinoma. The clinical trial collaboration will focus on evaluating the investigational combination in second line Renal Cell Carcinoma and second line Head and Neck Squamous Cell Carcinoma. WALTHAM, Mass., May 21, 2024 /PRNewswire/ -- Dragonfly Therapeutics, Inc., a clinical stage biotechnology company developing novel immunotherapies, today announced that it has entered into a clinical collaboration with Merck (known as MSD outside the US and Canada), to evaluate DF9001, Dragonfly's EGFR immune engager, in combination with Merck's anti-PD-1 therapy , KEYTRUDA® (pembrolizumab), in patients with advanced solid tumors expressing EGFR. "Merck, a trusted leader in drug development, has been a wonderful collaborator with Dragonfly since we signed our first collaboration agreement in 2018," said Bill Haney, co-founder and CEO of Dragonfly Therapeutics. "We are pleased to enter into this agreement with Merck for our ongoing, investigational Phase 1 trial of DF9001. In preclinical models, DF9001 engages multiple immune effector cells to drive anti-tumor activity and induces PD-L1 expression in tumor cells, sensitizing cold tumors to checkpoint inhibitors. We are hopeful that DF9001 in combination with KEYTRUDA will drive potent anti-tumor activity in a broad range of indications and are excited to further accelerate progress in the clinic to benefit patients in need." Dragonfly is the study sponsor and first patients are expected to receive DF9001 in combination with pembrolizumab in Q4 2024. Clinical trial sites are currently open for monotherapy dosing in the U.S., with additional sites in North America and Europe expected to open in 2024. Additional information about the trial, including eligibility criteria, can be found at: (ClinicalTrials.gov Identifier: NCT 05597839). KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. About DF9001 DF9001 is an investigational first-in-class multi-specific drug candidate that targets EGFR and potently redirects natural killer (NK) cells, gamma-delta T cells, and CD8 T cells by engaging activating receptors NKG2D and CD16. DF9001 was discovered and developed using Dragonfly's TriNKET ® platform. DF9001 is being evaluated in adult patients for the treatment of advanced solid EGFR-positive tumors. DF9001 has the potential to stimulate anti-tumor immunity in patients who are not eligible or not adequately responding to current therapies. DF9001 is the second wholly owned drug candidate in a pipeline of TriNKETs that Dragonfly is developing to address high unmet needs for patients across a broad range of disease areas. About Dragonfly Dragonfly Therapeutics is a clinical-stage biopharmaceutical company committed to discovering, developing and commercializing novel therapies that harness the body's immune system to bring breakthrough treatments to patients. In addition to a set of advanced programs in the clinic, Dragonfly has a deep pipeline of wholly owned preclinical candidates discovered using its proprietary platforms that are progressing toward the clinic, as well as productive collaborations with AbbVie, Bristol Myers Squibb, Gilead and Merck in a broad range of disease areas. For more information visit: DRAGONFLY MEDIA CONTACT: Anne E. Deconinck | [email protected] Logo -

Pictured: a collage of white blood cells and cancer cells/Taylor Tieden for BioSpace As their name suggests, natural killer (NK) cells intrinsically recognize and kill stressed cells, such as cancer cells. NK cells are not a new approach to treating cancer, but a novel class of antibodies is giving them a leg up in the fight, and drugmakers, including 23andMe and Innate Pharma, are leveraging this approach to develop cell therapies for a range of cancers. NK cells have a number of receptors that recognize specific stress ligands present on cancer cells, Lewis Lanier, a professor in microbiology and immunology at the University of California, San Francisco, told BioSpace. Antibody-based therapies promote NK cells’ anti-tumor activity by manipulating the receptor-ligand interactions and help NK cells to infiltrate the tumor site. While their approaches are different, both 23andMe and Innate are developing such therapies to activate the intrinsic ability of NK cells to recognize and kill tumor cells. Uncovering a Novel I-O Target Best known as a direct-to-consumer genetic testing company, 23andMe was founded in April 2006. Since then, the company has developed one of the largest databases of consumer genetic data. Jennifer Low, head of therapeutics development at 23andMe, told BioSpace that 80% of customers have consented to provide their health data, “including health experiences, family histories, their activities and medical records.” The company’s genetic database comprises genotypic and phenotypic data from 15 million people, including information about genetic variants, which informs its in-house drug discovery programs as well as programs initiated through collaborations, Low said. Specifically, the database contains information about parts of the genome that might provide insight for the development of novel immuno-oncology therapies, she noted. “The real problem with developing cancer therapies is that you need a target that’s not expressed on healthy tissues,” Lanier said. “If people can look through these massive datasets and find evidence for the overexpression of certain tumor ligands, that can be exploited therapeutically.” Earlier this month at the American Association for Cancer Research’s annual meeting, 23andMe presented data on its two clinical-stage programs. One, an antibody called 23ME-01473, targets soluble ULBP6, a dominant immunosuppressor shed by tumor cells. The novel target, discovered using the company’s genetic and health survey database, is a ligand for NKG2D, an NK cell surface receptor that recognizes a wide array of stress-associated ligands expressed on tumor cells. Tumor cells shed ULBP6 into the tumor microenvironment to bind NKG2D, bypassing recognition by NK cells. Blocking ULBP6-NKG2D binding may thus restore immune cell recognition and killing of cancers, according to 23andMe. “There is some data suggesting ULBP6 is overexpressed in some tumors,” Lanier said, adding that using an antibody against ULBP6 is a “good strategy.” In addition to targeting the ULBP6-NKG2D interaction, Low said, 23andMe’s investigational antibody also has an Fc-effector-enhanced region capable of engaging NK cells and further enhancing their function. 23andMe initiated a Phase I clinical trial in March 2024 to evaluate the safety and tolerability of 23ME-01473 in patients with advanced solid tumors that have progressed on standard-of-care treatments. NK Cell Engagers Biopharma has long recognized the potential of NK cells. Lately in the cell and gene therapy space, NK cell therapies have captured attention. The global NK cell therapy market stood at $92 million in 2022 and is projected to reach $3.1 billion by 2031. But even short of infusing these natural killers into cancer patients, several companies are looking to harness NK cell biology to fight cancer. In addition to 23andMe, other players in this space include Dragonfly Therapeutics, D2M Biotherapeutics and Innate Pharma. “Our therapeutic strategies have two main focuses: Unleashing NK cells or stimulating NK cells via NK cell engagers,” Eric Vivier, SVP and chief scientific officer of Innate, told BioSpace. Innate’s lead asset, IPH6101/SAR443579, being developed in partnership with Sanofi, is an antibody-based NK cell engager directed against NK cell receptors NKp46 and CD16 and against the tumor antigen CD123, which is overexpressed in acute myeloid leukemia (AML). Vivier explained the rationale behind the selection of the two NK cell receptors. “NKp46 is a stably expressed activating receptor found on NK cells," and CD16 is a receptor for antibodies that also stimulates NK cell function. Innate and Sanofi kicked off a Phase II dose expansion trial of IPH6101/SAR443579 last week. The companies plan to recruit 126 patients with AML, B-cell acute lymphoblastic leukemia, and high-risk myelodysplasia, among other cancers. Vivier said NK cell engagers have a possible advantage over T cell engagers as they do not induce a cytokine storm—a severe immune response leading to the excessive release of pro-inflammatory cytokines, organ damage and mortality—common to the latter. Another candidate, IPH6501 is an NK cell engager that also targets NKp46 and CD16, plus the tumor antigen CD20, and is armed with a variant of interleukin 2 (IL-2). Adding cytokines such as IL-2 to the NK cell engager induces cell proliferation pathways and boosts immune response, Vivier explained. Lanier agreed. While NK cell engagers draw NK cells from the blood to the tumor, NK cells that make it into tumors get shut down by the immunosuppressive microenvironment, he noted. “Introducing cytokines wakes up NK cells and restores their functionality.” In preclinical studies, IPH6501 showed “massive infiltration” of NK cells to the tumor and good tumor growth control, Vivier said. Safety and tolerability of the asset is currently being evaluated in a Phase I clinical trial for patients with relapsed/refractory non-Hodgkin’s lymphoma, with initial data expected in 2025. A 2023 article published in the Journal of Hematology & Oncology posits that T-cell engagers “will likely revolutionize the treatment of hematological malignancies in the short term, as they are considerably more potent than conventional monoclonal antibodies recognizing the same tumor antigens.” Bispecific NK cell engagers offer similar efficacy with milder side effects, the authors note, and trispecific antibodies “raise the game even further.” “Altogether, these engineered molecules may change the paradigm of treatment for relapsed or refractory hematological malignancies,” the authors write. Sunitha Chari is a freelance science writer and academic editor based in Toronto. See more of her work at sunithachari.contently.com and reach her at sunithachari.02@gmail.com. Correction (April 22): This article has been updated from its original version to correct that Eric Vivier is SVP and chief scientific officer of Innate Pharma, not president and CEO. BioSpace regrets the error.