CD70

The CD19/CD70 Dual CAR is Specifically Designed to Address Both the B-cell and T-cell Dysfunction Implicated in Autoimmune Diseases ALLO-329, is an Investigational Product Built on a New Gene Editing Platform that Features Site-Specific Integration, Intended to Reduce the Risk of Secondary Malignancies, and Leverage the Clinically Validated Dagger® Effect Aimed at Reducing or Eliminating Lymphodepletion, a Potential Barrier in the Adoption of CAR T in Autoimmune Indications Sept. 26, 2024 -- Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T™) products for cancer and autoimmune disease, today announced that it will present pre-clinical data for its next-generation investigational AlloCAR T candidate for autoimmune indications, ALLO-329, at the American College of Rheumatology's annual meeting, ACR Convergence 2024, being held from November 14-19 in Washington, D.C. ALLO-329, the Company’s CD19/CD70 dual AlloCAR T product is the first CAR T designed to both reduce or eliminate the need for lymphodepletion while also targeting CD19+ B-cells and CD70+ activated T-cells, both of which are likely to play a role in autoimmune diseases. ALLO-329 utilizes CRISPR-based site-specific integration for dual CAR expression. “We are at the beginning of understanding what may be possible for CAR T in autoimmune disease. However, the only way to fully realize the potential of the modality is to develop product candidates designed to meet the specific needs of this vast patient population and allow for greater implementation in real-world practice. This is how we have designed ALLO-329,” said Zachary Roberts, M.D., Ph.D., Executive Vice President of Research & Development of Allogene. “We believe the first and most important factor for the potential success of CAR T in autoimmune disease is being available off-the-shelf to meet potential demand. Next, we have addressed lymphodepletion by incorporating our proprietary and clinically validated Dagger® technology, which is designed to enable cells to expand and persist in patients without or with potentially reduced chemotherapy conditioning. Lastly, our dual CAR targets both the B- and T-cell components of autoimmune disease, which we believe may allow for a broader application of CAR T across a multitude of indications.” Title: Preclinical Evaluation of ALLO-329: Allogeneic CD19 CAR T Cells Expressing an Anti-Rejection CD70 CAR for the Treatment of Autoimmune Diseases Presenter: Kristen Zhang, Research Scientist, Allogene Therapeutics Abstract Number: 1841 Poster Session: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster Date and Time: Monday, November 18, 10:30 a.m-12:30 p.m. ET The abstract can be found on the American College of Rheumatology’s website. The Company plans to file an investigational new drug (IND) application with the U.S. Food and Drug Administration in the first quarter of 2025 and expects to have proof-of-concept by year-end 2025. Allogene Therapeutics, with headquarters in South San Francisco, is a clinical-stage biotechnology company pioneering the development of allogeneic chimeric antigen receptor T cell (AlloCAR T™) products for cancer and autoimmune disease. Led by a management team with significant experience in cell therapy, Allogene is developing a pipeline of “off-the-shelf” CAR T cell product candidates with the goal of delivering readily available cell therapy on-demand, more reliably, and at greater scale to more patients. For more information, please visit www.allogene.com, and follow Allogene Therapeutics on X (formerly Twitter) and LinkedIn. The content above comes from the network. if any infringement, please contact us to modify.

Molecular Partners is changing the protocol in an early-phase to allow higher and more frequent dosing. Molecular Partners has identified “suboptimal exposure” to its tetra-specific T-cell engager as the potential cause of the limited response rate in its early-phase trial, prompting the Swiss biotech to change the protocol to try to dial up the impact of the compound.The candidate, MP0533, features six binding domains. Three of the domains engage CD33, CD123 and CD70 on the target tumor cells. One domain targets CD3 to engage T cells, and the final two domains are there to prolong the half-life of the candidate in circulation. Molecular Partners picked the tumor targets to kill cancer cells that express two or more antigens while sparing healthy, single-expressing cells. Investigators are testing the candidate in a phase 1/2a study that is enrolling patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. As of July 29, the biotech had seen four clinical responses in the 28 patients treated in the first six dose cohorts.Philippe Legenne, M.D., fresh from his appointment as Molecular Partners’ permanent chief medical officer, walked through the interim data on an earnings call Tuesday. After discussing the number of responses, Legenne concluded that the company “need[s] to have more than that to be completely satisfied and to qualify that we would unlock the potential of that compound.” Molecular Partners has identified “suboptimal exposure” as a barrier to realizing the full potential of the candidate. That observation led the biotech to prepare to change the protocol to allow higher and more frequent dosing in pursuit of improved response rate, depth of response and durability. Investigators are now enrolling patients in the eighth dose cohort and could go up to the eleventh dose level.“What we hope is that we are going to ... reduce the tumor ... burden. We see that we have more responses in the lower tumor burden than in the higher,” Legenne said. “We also want to avoid by design having chronic exposure, because we are also conscious of that concept of T-cell exhaustion. So we wouldn't want to be continuous all the time. Then the question is how little is enough.”One outstanding question is whether increasing the dose will improve the responses. Molecular Partners saw one complete response on the fourth dose and one case of morphologic leukemia-free state at the third, fifth and sixth doses. The biotech is still collecting data on the seventh dose, but, at this stage, there is no clear dose response. 

In one clinical trial, 120 mg of Belzutifan (n=374) or 10 mg of everolimus (n=372) were taken orally once daily until disease progression or unacceptable toxic reactions occurred. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the key secondary endpoints were objective response rate (ORR), including confirmed complete response (CR) or partial response (PR). The first interim analysis (median follow-up period was 18.4 months) revealed that the median PFS in both groups was 5.6 months. At 18 months, 24.0% of participants in the Belzutifan group and 8.3% in the active control group were alive and without disease progression (P=0.002). In addition, the objective response rate of patients in the Belzutifan group was 6 times higher than that in the active control group. Specifically, 21.9% of patients in the Belzutifan group (95% CI: 17.8-26.5) achieved an objective response, compared to only 3.5% (95% CI: 1.9-5.9) in the active control group, a statistically significant difference (P<0.001). In the second interim analysis, with a median follow-up of 25.7 months, the median OS was 21.4 months in the Belzutifan group and 18.1 months in the active control group. At 18 months, 55.2% and 50.6% of subjects were alive, respectively (HR=0.88; 95% CI: 0.73-1.07; P=0.20). In terms of safety, 61.8% of patients in the Belzutifan group (3.5% grade 5) and 62.5% of patients in the active control group (5.3% grade 5) experienced grade 3 or higher adverse events. Treatment was discontinued due to adverse events in 5.9% and 14.7% of participants, respectively. There were no new safety signals at Belzutifan. Belzutifan, the first HIF-2α inhibitor to receive accelerated FDA approval, has been approved in the United States of America, the United Kingdom of Great Britain and Northern Ireland, Canada, and several other countries for the treatment of adults with von Hippel-Lindau (VHL) disease. This is especially true for those with associated renal cell carcinoma (RCC), central nervous system hemangioblastoma, or pancreatic neuroendocrine tumors that do not require immediate surgery. In December 2023, Belzutifan became the first HIF-2α inhibitor to be approved for use in patients with advanced RCC, marking the first time since 2015 that a new mechanistic therapy for advanced RCC has been approved. Merck is committed to expanding the application potential of Belzutifan, and actively promote Belzutifan alone or in combination with PD-1 inhibitor Pembrolizumab in RCC, endometrial cancer, esophageal cancer, liver cancer, prostate cancer and rare cancers. At present, Belzutifan has entered the second phase of clinical trials for endometrial cancer, esophageal cancer, liver cancer, prostate cancer and rare cancers, and we look forward to more good news to benefit more patients at an early date. At the same time, the industry continues to promote the development of RCC therapies. In addition to Belzutifan, there are currently several RCC therapies in clinical development. In terms of small molecule therapies, Zanzalintinib, a new generation of oral TKI therapy developed by Exelixis, has attracted much attention. Zanzalintinib inhibits tyrosine kinase activity in receptors associated with cancer growth and spread, including VEGF receptors, MET, AXL, and MER. Results from the Phase 1b trial, published in November, showed that at a median follow-up of 8.3 months, 12 of 32 treated clear cell RCC patients enrolled in the extended cohort achieved a confirmed PR, with an ORR of 38% and a disease control rate (DCR) of 88%. Fruzaqla (Fruquintinib, fuquinitinib), a VEGFR-1, -2 and -3 inhibitor developed by HUTCHMED and Takeda, is also being examined in a registered study for the treatment of RCC patients. In recent years, the rise of new molecular therapies has brought new hopes for the potential treatment of RCC patients. The most notable of these is the personalized mRNA cancer vaccine MRNA-4157 (V940), jointly developed by Moderna and Merck, which has recently started a phase 2 study for the treatment of patients with RCC. In May, Arsenal Biosciences announced that AB-2100, its T-cell therapy for patients with clear cell RCC, had completed its first patient administration in a multicenter, open-label phase 1/2 clinical trial. AB-2100 uses the company's CITE (CRISPR Electroporation Integrated Transgene) technology to engineer T cells so that they can selectively target tumors and overcome the inhibitory tumor microenvironment. These properties make it possible for the patient's immune system to destroy RCC cells without harming normal tissue. In addition, Adicet Bio announced in June that its gamma-δ CAR-T cell candidate for CD70-positive cancer, ADI-270, is scheduled to initiate a Phase 1 clinical trial for relapsed/refractory RCC in the second half of 2024. To evaluate the safety and antitumor activity of ADI-270 in patients with RCC.