XRCC1

After the early wave of immunotherapies proved successful at treating certain cancers, the race has been on to broaden the treatable patient population by fine-tuning specificity and tamping down on toxicities, particularly in solid tumours – and Janux Therapeutics may have just taken the lead for next-generation T-cell engagers. The biotech skyrocketed nearly 230% Tuesday after its two programmes seemed to avoid the severe safety side effects that have hampered the modality’s movement into solid tumours. In a pair of Phase Ia, dose-escalating studies, Janux’s conditional T-cell engagers, called Tumor Activated T Cell Engagers (TRACTrs), did not lead to any cases of high-grade cytokine release syndrome (CRS), “a major toxicity issue that led to discontinuation of multiple T-cell engager clinical candidates,” H.C. Wainwright analysts wrote in a note. “The positive initial data provides validation for the double-masking approach,” they added.Janux’s ‘masking’ technology was developed to ensure tumour-specific activation and avoid on-target toxicities. Both of the clinical TRACTrs comprise a tumour antigen-binding domain and CD3, the latter of which is covered by a peptide mask that can only be removed by tumour-specific proteases. This prevents T-cell binding before the treatment reaches its target, avoiding an overactive immune response. Similarly, TRACTrs also have an albumin binding domain mask to extend half-life, and these can only be removed at the tumour as well.Competitive prostate cancer dataThe first programme, dubbed JANX007, is a PSMA-targeted TRACTr intended to treat advanced or metastatic castration-resistant prostate cancer (mCRPC). So far, 23 patients have received the treatment, and a maximum tolerable dose has yet to be reached. Janux said reported incidents of CRS were “temporary and mild,” with no events higher than Grade 2.At the ≥0.1mg starting dose, 10 of 18 (56%) patients saw a PSA reduction from baseline of at least half, and the next dose level of  ≥0.2mg led to the same PSA reduction in 5 of 6 (83%) evaluable patients. The H.C. Wainwright analysts suggested these results compare favourably with Pluvicto (lutetium Lu 177 vipivotide tetraxetan), a PSMA-targeting radiotherapeutic from Novartis, which was approved by the FDA after demonstrating that 177 of 385 (46%) mCRPC patients experienced a PSA reduction of  50% or more. Janux plans on sharing updated dose expansion data next half.Lung cancer responds Janux’s second candidate is solid tumour-agnostic. JANX008 targets EGFR and is being studied in patients with advanced or metastatic cancers including colorectal cancer, squamous cell carcinoma of the head and neck, non-small-cell lung cancer (NSCLC), and renal cell carcinoma (RCC).Of the 11 treated patients, only two experienced CRS, and both cases were classified as Grade 1. One patient with NSCLC who received a once-weekly 0.15mg dose of JANX008 had a confirmed partial response (PR), with 100% reduction of their lung lesion, elimination of liver metastasis, and no CRS. The PR was maintained through their week-18 scan. Additionally, one patient experienced a 12% reduction of their RCC mass. The company said it is continuing the dose escalation and optimisation of JANX008.

NEW YORK, Aug. 9, 2023 /PRNewswire/ -- The DeGregorio Family Foundation with the support of the Price Family Foundation and the Esophageal Cancer Awareness Association has awarded $87,500 to Dawit Kidane-Mulat, PhD, Associate Professor at Howard University College of Medicine to complete his grant. Dr. Kidane-Mulat is working to enhance the effectiveness of immunotherapy in gastric cancers, which now has a very low success rate, in the five percent range. Continue Reading Dr. Dawit Kidane-Mulat The overarching goal of this study is to harness XRCC1-deficient gastroesophageal cancer cells that will likely enhance the efficacy of immunotherapy response. Dr. Kidane-Mulat is examining how defective XRCC1 and targeting DNA damage response contributes to aberrant innate immune cells inflammatory response. He and his lab are pursuing how inhibition of ATM activity in XRCC1 deficient/low expressing gastric cells induces DNA sensor cGAS/STING mediated aberrant inflammatory response. This work lays the foundation for additional in-depth preclinical studies, and for the development of novel therapeutic strategies for stomach cancer. Commenting on his award, Dr. Kidane-Mulat said, "I am grateful to the DeGregorio Family Foundation. As a result of this award, I am generating a long line of research into understanding the basis of DNA repair/response and immunotherapy treatment in stomach cancer. This grant award is opening a new opportunity to propel the field forward and build a solid foundation for future immunotherapy therapeutic strategies in gastric cancer." In 2020, gastric and esophageal cancers combined to kill over 1.3 million people worldwide— making it the second-leading cause of cancer-related deaths. Patients continue to face poor prognoses following gastric and esophageal cancer diagnoses due to their chemo-resistant behavior and ability to metastasize. "Dr. Kidane-Mulat's grant could be paradigm-changing," concluded Lynn DeGregorio, President and Founder. "We're honored to fund deserving research like this that has the potential to significantly improve how we treat gastroesophageal cancers." The DeGregorio Family Foundation, founded in 2006 after a 10th member of the DeGregorio family died of stomach cancer, has raised more than $8 million to fund innovative research focused on curing gastric and esophageal cancers. It is the only foundation funding research grants for both of these cancers. SOURCE DeGregorio Family Foundation

– ARTISTRY-1 Data Showed Anti-Tumor Activity of Nemvaleukin, as a Monotherapy and in Combination with Pembrolizumab, in Multiple Tumor Types – – Company to Host Investor Webcast on June 6 at 8:00 a.m. ET – DUBLIN, June 1, 2022 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today announced plans to present data from the ARTISTRY-1 clinical trial for nemvaleukin alfa (nemvaleukin), the company's novel, investigational, engineered interleukin-2 (IL-2) variant immunotherapy. The data will be presented in an oral presentation at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place June 3-7, 2022 in Chicago and virtually, and in an investor webcast hosted by the company on June 6, 2022. The presentations will include efficacy and safety data from ARTISTRY-1, a phase 1/2 study evaluating the safety, tolerability and efficacy of nemvaleukin administered intravenously as a monotherapy and in combination with pembrolizumab (KEYTRUDA®). In this study, nemvaleukin demonstrated anti-tumor activity with durable responses as monotherapy in checkpoint inhibitor (CPI)-experienced melanoma and renal cell carcinoma (RCC) patients and as combination therapy in pretreated patients across a range of difficult-to-treat tumors, including in tumor types where CPIs have had limited clinical benefit, and in CPI-experienced patients. Treatment-related adverse events (AEs) were mostly transient and manageable. "The results of ARTISTRY-1 demonstrate that selectively targeting the IL-2 pathway may deliver significant clinical benefit in multiple tumor types while mitigating the hallmark toxicities associated with high-dose recombinant-IL-2," said Ulka N. Vaishampayan, M.D., Professor, Internal Medicine, Division of Hematology/Oncology, University of Michigan. "These data specifically highlight the potential clinical utility of nemvaleukin as a monotherapy and in combination with pembrolizumab in heavily pretreated patients across multiple tumor types, including in mucosal melanoma and platinum-resistant ovarian cancer." "ARTISTRY-1 provided important data that has revealed nemvaleukin's pharmacokinetic and pharmacodynamic profile, exhibited similar monotherapy anti-tumor activity as seen with high-dose IL-2, demonstrated anti-tumor activity in combination with a CPI, and established a differentiated safety and tolerability profile," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "As we focus on enrolling our potential registrational studies, ARTISTRY-6 in mucosal melanoma and ARTISTRY-7 in platinum-resistant ovarian cancer, these data from ARTISTRY-1 further reinforce our understanding of nemvaleukin's pro our belief in its clinical potential." Data highlights from the ASCO oral presentation and the company's investor presentation include the following (all data are as of the Oct. 29, 2021 ASCO data cutoff date, unless otherwise noted): ARTISTRY-1, Nemvaleukin IV Monotherapy The ARTISTRY-1 monotherapy cohorts included heavily pretreated, CPI-experienced patients with advanced melanoma or RCC. Melanoma monotherapy cohort (46 evaluable patients): Six patients achieved a partial response (PR), of which three were confirmed. Two of the six PRs were reported after the ASCO data cutoff date. Stable disease (SD) was observed in 31 patients. All melanoma patients who achieved a PR with nemvaleukin monotherapy had previously progressed on CPI treatment. Out of six evaluable mucosal melanoma patients, two patients achieved a PR (one confirmed). One of these two patients who achieved a PR remained on nemvaleukin monotherapy for more than two years, with a duration of response (DOR) of 79 weeks. RCC monotherapy cohort (22 evaluable patients): Four patients achieved a PR, of which three were confirmed. Three of the patients who achieved a PR remained on nemvaleukin monotherapy for a range of 24 – 63 weeks. SD was observed in 10 patients. All RCC patients who achieved a PR with nemvaleukin monotherapy had previously progressed on CPI treatment. ARTISTRY-1, Nemvaleukin IV in Combination With Pembrolizumab The ARTISTRY-1 combination cohorts included patients with PD-1/L1 unapproved tumor types; patients with PD-1/L1 approved tumor types (PD-1/L1 pretreated and PD-1/L1 treatment naïve) as well as tumor-specific cohorts and a cohort for patients who rolled over into a combination cohort from a monotherapy cohort. Among the 137 total evaluable patients, four complete responses (CRs) and 18 PRs were observed, SD was observed in 60 patients, and overall median DOR was 23 weeks. In the PD-1/L1 unapproved cohort (36 evaluable patients): Two patients achieved a CR, four patients achieved a PR and SD was observed in 14 patients. Both of these CRs and two of these PRs (one confirmed), were in patients with platinum-resistant ovarian cancer (PROC) (out of 14 evaluable PROC patients in this cohort). Median DOR in the PROC cohort was 53 weeks. In the PD-1/L1 approved cohorts (total 43 evaluable patients): Among 22 evaluable pretreated patients, one patient achieved a PR and SD was observed in 10 patients. Among 21 evaluable PD-1/L1 naïve patients, one patient achieved a CR, six patients achieved PRs and SD was observed in seven patients. Treatment-related adverse events (TRAEs) across the ARTISTRY-1 study were consistent with those previously reported for the IV nemvaleukin monotherapy and combination therapy-treated populations from the trial. Pyrexia, chills and neutropenia/decreased neutrophil count were the most commonly reported TRAEs. Across the ARTISTRY-1 study, nemvaleukin in combination with pembrolizumab demonstrated no additive toxicity compared to pembrolizumab alone and no event of capillary leak syndrome was reported. "Immunotherapies have revolutionized cancer treatment, but significant unmet need remains, as many patients are not eligible or do not respond to certain immunotherapies such as checkpoint inhibitors. Broadening the benefits of immunotherapy to a wider range of patients is an important goal for the treatment community and cancer researchers," said Jill O'Donnell-Tormey, Ph.D., Chief Executive Officer and Director of Scientific Affairs, Cancer Research Institute. "These data from ARTISTRY-1, particularly in patients who are not eligible for current immunotherapies such as a PD-1/L1 inhibitor or who have progressed following treatment with immunotherapies, suggest that nemvaleukin may provide clinical benefit in this patient population. These data support further evaluation of nemvaleukin in future studies." Trial-in-progress posters from the ongoing ARTISTRY-3 trial and the potential registration-enabling ARTISTRY-6 and ARTISTRY-7 trials will also be presented at the ASCO meeting. All presentations are available on the ASCO website at . Oral Presentation Abstract: 2500 Title: Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1 Presenter: Ulka N. Vaishampayan, M.D., Professor, Internal Medicine, Division of Hematology/Oncology, University of Michigan Presentation Date/Time: The oral presentation will take place on Saturday, June 4, 2022 from 1:15 – 4:15 p.m. CDT, during the session titled "Developmental Therapeutics—Immunotherapy" Poster Presentations Abstract: TPS5609 Title: ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa in combination with pembrolizumab versus chemotherapy in patients (pts) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer Presenter: Thomas J. Herzog, M.D., Professor of Obstetrics and Gynecology, Deputy Director, University of Cincinnati Cancer Institute and Associate Director of GOG Partners Presentation Session Date/Time: The poster will be presented on Saturday, June 4, 2022 from 1:15 – 4:15 p.m. CDT, during the "Gynecologic Cancers" poster session Abstract: TPS2684 Title: ARTISTRY-3: Effect of nemvaleukin alfa with a less frequent IV dosing schedule as monotherapy and in combination with pembrolizumab and impact on the tumor microenvironment (TME) in patients (pts) with advanced solid tumors Presenter: Sarina A. Piha-Paul, M.D., Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center Presentation Session Date/Time: The poster will be presented on Sunday, June 5, 2022 from 8:00 – 11:00 a.m. CDT, during the "Developmental Therapeutics—Immunotherapy" poster session Abstract: TPS9609 Title: ARTISTRY-6: Nemvaleukin alfa monotherapy in patients with advanced mucosal and cutaneous melanoma Presenter: Jeffrey S. Weber, M.D., Ph.D., Professor of Medicine, Deputy Director, Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine Presentation Session Date/Time: The poster will be presented on Monday, June 6, 2022 from 1:15 – 4:15 p.m. CDT, during the "Melanoma/Skin Cancers" poster session Conference Call and Webcast Alkermes will host a webcast presentation and conference call with accompanying slides for analysts and investors on Monday, June 6, 2022, at 8:00 a.m. ET (1:00 p.m. BST) to discuss data from the ARTISTRY-1 clinical trial and the ARTISTRY clinical program. The webcast will feature ARTISTRY clinical program investigators, Ulka N. Vaishampayan, M.D., Professor, Internal Medicine, Division of Hematology/Oncology, University of Michigan; Omid Hamid, M.D., Co-director of Cutaneous Oncology, Director of Melanoma Therapeutics and Phase I Immuno-oncology Program, Chief of Translational Research and Immunotherapy, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles; Thomas J. Herzog, M.D., Professor of Obstetrics and Gynecology, Deputy Director University of Cincinnati Cancer Institute, Associate Director of GOG Partners; and members of Alkermes' management team. The webcast player may be accessed on the Investors section of Alkermes' website at . To participate in the question-and-answer session, please also dial in to the conference call, which may be accessed by dialing +1 877-407-2988 for U.S. callers and +1 201-389-0923 for international callers. A replay of the webcast will be archived on the company's website for 30 days following the presentation. About Nemvaleukin Alfa (nemvaleukin) Nemvaleukin is an investigational, novel, engineered fusion protein comprised of modified interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor chain, designed to preferentially expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by selectively binding to the intermediate-affinity IL-2 receptor complex. The selectivity of nemvaleukin is designed to leverage the proven anti-tumor effects of existing IL-2 therapy while mitigating certain limitations. About the ARTISTRY Clinical Development Program ARTISTRY is an Alkermes-sponsored clinical development program evaluating nemvaleukin as a potential immunotherapy for cancer. The ARTISTRY program is comprised of multiple clinical trials evaluating intravenous and subcutaneous dosing of nemvaleukin, both as a monotherapy and in combination with the anti-PD-1 therapy KEYTRUDA® (pembrolizumab) in patients with advanced solid tumors. Trials in the ARTISTRY program include: ARTISTRY-1, ARTISTRY-2, ARTISTRY-3, ARTISTRY-6 and ARTISTRY-7. About Alkermes plc Alkermes plc is a fully-integrated, global biopharmaceutical company developing innovative medicines in the fields of neuroscience and oncology. The company has a portfolio of proprietary commercial products focused on alcohol dependence, opioid dependence, schizophrenia and bipolar I disorder, and a pipeline of product candidates in development for neurodegenerative disorders and cancer. Headquartered in Dublin, Ireland, Alkermes plc has a Research & Development center in Waltham, Massachusetts; a research and manufacturing facility in Athlone, Ireland; and a manufacturing facility in Wilmington, Ohio. For more information, please visit Alkermes' website at . Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning the potential clinical value and utility of nemvaleukin as an immunotherapy, whether as monotherapy or in combination, in multiple tumor types. You are cautioned that forward-looking statements are inherently uncertain. Although the company believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, the forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others, whether nemvaleukin could be shown to be unsafe or ineffective; whether results and data from clinical studies for nemvaleukin will be predictive of future or final results from such studies, results of future clinical studies or real-world results; whether future clinical trials or future stages of ongoing clinical trials for nemvaleukin will be initiated or completed on time or at all; changes in the cost, scope and duration of, and clinical trial operations for, development activities for nemvaleukin, including changes relating to the impact of the novel coronavirus (COVID-19) pandemic; and those risks and uncertainties described under the heading "Risk Factors" in the company's Annual Report on Form 10-K for the year ended Dec. 31, 2021, and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC's website at . Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release. KEYTRUDA® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Alkermes Contacts: For Investors: Sandy Coombs +1 781 609 6377 For Media: Sourojit Bhowmick, Ph.D. +1 781 609 6397 Company Codes: NASDAQ-NMS:ALKS