IL-3

Researchers have not only identified how two immune cells work together to fight cancer but also revealed the cascade of molecules that help coordinate this attack. The ecosystem that surrounds a tumor, also known as the tumor microenvironment, includes immune cells, tissues, blood vessels and other cells that interact with each other and with the tumor. Over time, the tumor shapes this ecosystem to its own benefit, monopolizing all of the nutrients and shielding it from immune attack. In working to understand the ecosystem's role in cancer risk, development and treatment, researchers at The Jackson Laboratory have not only identified how two immune cells work together to fight cancer but also revealed the cascade of molecules that help coordinate this attack. The work, led by JAX Assistant Professor Chih-Hao "Lucas" Chang, Ph.D., focuses on cytotoxic T-cells, a type of immune cell with many functions, including destroying cells infected with viruses and fighting bacterial infections and other pathogens. They also attack tumor cells. Our immune systems are able to eliminate most cancerous cells from our body before they can cause a problem. But once a tumor becomes established, cytotoxic T-cells become "exhausted" in the hostile tumor microenvironment and unable to effectively attack tumors. Chang and colleagues are investigating why these immune cells become exhausted, and potential ways to signal them back to targeting tumors. "T-cells are excellent at identifying and attacking cells that become cancerous, but they can become exhausted in the tumor microenvironment; they can become overworked and overstimulated, while also being starved of glucose and other nutrients by tumor cells. Helping these cells to function better could improve cancer treatment strategies, particularly immunotherapies," said Chang, whose work appears in Cancer Immunology Research. Previous studies showed that when cytotoxic T-cells are activated, they release signaling molecules called cytokines. Chang and colleagues focused on one of these cytokines, interleukin-3 (IL-3), discovering that as a tumor grows, cytotoxic T-cells progressively lose the ability to produce IL-3 in the tumor microenvironment. Then, when Chang elevated IL-3 levels in mice bearing lymphoma or melanoma tumors, he observed strong antitumor effects. Chang's team further revealed that IL-3 works to mobilize basophils, a rare immune cell that can also play a role in allergies. In turn, these basophils produce another cytokine known as interleukin-4 (IL-4), which reenergizes cytotoxic T-cells, signaling them to resume detecting and destroying tumors. "Basophils have not previously been implicated in the signaling cascade for reinvigorating cytotoxic T-cells," said Chang. "These findings are preliminary, but targeting tumor-associated basophils represents a promising avenue for enhancing antitumor immunity and improving patient outcomes."

Pictured: Illustration of lungs with syringes/Nicole Bean for BioSpace Potential FDA approvals this year of Sanofi and Regeneron’s Dupixent (dupilumab), as well as Verona Pharma’s ensifentrine, could change the treatment paradigm for chronic obstructive pulmonary disease, according a new report from analytics firm GlobalData. Dupixent is poised to address the notable gap in biologic treatments for chronic obstructive pulmonary disease (COPD) and target its underlying inflammatory pathway by blocking the IL-3 and IL-4 cytokines, according to the analysis. Meanwhile, Verona’s ensifentrine introduces a new mechanism by inhibiting both the phosphodiesterase 3 and 4 enzymes to ease exacerbations. “The COPD late-stage market looks extremely promising,” GlobalData pharma analyst Asiyah Nawab said in a statement, adding that their modes of action and promising clinical data could facilitate their “penetration into the market this year.” According to COPD experts interviewed by GlobalData, “the pipeline for COPD is extremely positive, with Sanofi/Regeneron’s Dupixent and Verona’s Ensifentrine having a high chance of being licensed.” The experts also noted that the COPD space “has not been in this position for decades.” Sanofi and Regeneron’s Dupixent—currently approved for atopic dermatitis, asthma, prurigo nodularis, eosinophilic esophagitis and chronic rhinosinusitis with nasal polyps—is a monoclonal antibody that blocks the IL-3 and IL-4 cytokines reducing type 2 inflammation, a key driver in several immune-mediated conditions. The partners are proposing Dupixent as a COPD treatment using results from the Phase III BOREAS and NOTUS trials. Data from BOREAS, published in May 2023, demonstrated that adding Dupixent to standard of care could reduce moderate or severe exacerbations by 30% over 52 weeks. The therapeutic antibody could also boost lung function and health-related quality of life while lowering symptom severity. In NOTUS, Dupixent reduced moderate or severe acute exacerbations by 34% over 52 weeks of follow-up, while also improving lung function. The FDA in February 2024 accepted the supplemental Biologics License Application for Dupixent and granted it Priority Review. The decision is due by June 27, 2024. Verona’s ensifentrine is also undergoing regulatory review. The FDA accepted its New Drug Application in September 2023 and has set a target action date of June 26, 2024. Ensifentrine is backed by data from the Phase III ENHANCE trials, which found that the candidate reduced the risk of COPD exacerbations while also improving lung function and easing symptoms. In January 2024, Verona secured $400 million in financing from Oxford Finance and Hercules Capital, which the biotech will use to fund the launch of ensifentrine. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

- Allogeneic CARCIK-CD19 therapy after hematopoietic stem cell transplantation relapse induced complete responses in 76.2 percent of 21 patients in the two highest dose groups - - 81.3 percent of complete responders in highest dose groups were minimal residual disease negative - - Additional presentations evaluate CAR-CIK strategy in acute myeloid leukemia - DURHAM, N.C., Dec. 13, 2022 /PRNewswire/ -- CoImmune, Inc., a clinical stage immuno-oncology company working to redefine cancer treatment using best-in-class cellular immunotherapies, today announced the presentation of results from a Phase I/II clinical trial evaluating CARCIK-CD19, an investigational treatment based on the company's chimeric antigen receptor (CAR) modified cytokine induced killer (CIK) cell platform, in pediatric and adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who had relapsed following hematopoietic stem cell transplantation (HSCT). The results are being presented at the American Society of Hematology's (ASH) 64th Annual Meeting and Exposition held December 10-13 in New Orleans. "For more than 15 years, we have been working to advance innovative pre-clinical and clinical research in the field of cellular and gene therapy for childhood and adult acute lymphoblastic leukemia, and these data presented at the ASH annual meeting represent a promising breakthrough," said Andrea Biondi, M.D., Professor of Pediatrics at the University of Milano-Bicocca and Scientific Director of the M. Tettamanti Research Center. "In the Phase I/II dose-finding study, CARCIK-CD19 cells demonstrated an excellent safety profile with anti-leukemia activity in heavily pretreated patients with B-ALL relapsed after HSCT. Importantly, the persistence of these cells was associated with a longer duration of response and reduced risk of leukemia relapse." The Phase I/II dose escalation clinical trial included 27 patients (4 children and 23 adults) with B-ALL relapsed post-HSCT, six of whom participated under a compassionate use protocol and received the highest dose level. The study was conducted as a collaboration between the Pediatric and Haematology Departments of Monza and Bergamo (Italy), respectively. Results show that 18 out of 27 patients (66.7%, 95%CI=46.0-83.5%) achieved complete response (CR), with 14 (77.8%) of the overall responders negative for minimal residual disease (MRD). In the two highest dose groups, 16 out of 21 patients (76.2%, 95%CI=52.8-91.8%) achieved CR, with 13 of the responders at the highest dose (81.3%) MRD-negative. The median follow-up was 2.8 years (range, 0.05-4.4 years, last update as of July 2022). Event-free survival (EFS) was significantly longer in the two highest dose groups (p=0.0265) and was associated with the percentage of bone marrow blasts after lymphodepletion (≥ 5% vs <5%) (p=0.0245). Graft versus host disease never occurred after treatment with CARCIK-CD19, and no dose limiting toxicity was observed. In a prospective study also presented at the ASH Annual Meeting, Giuseppe Gaipa, Ph.D., and Benedetta Rambaldi, M.D., Ph.D., evaluated the impact on clinical outcome of proliferation, differentiation, and expansion of CARCIK-CD19 cells in 20 of the patients treated in Phase I/II clinical trial. The cells were detectable up to 12 months in vivo, a majority of which presented with CD8+ memory phenotype. Their persistence after day 90 was correlated with duration of response (p=0.0045), and MRD-negativity was associated with longer survival (p=0.004). CoImmune is also announcing the presentation two additional preclinical studies at the ASH Annual Meeting that evaluated the CAR-CIK strategy in acute myeloid leukemia (AML). Both were performed at the M. Tettamanti Research Center, Monza, Italy. In a poster titled, "Tuned IL3-Zetakine Coupled to a CD33 Costimulatory Receptor As a Dual CAR for Safer and Selective Targeting of Acute Myeloid Leukemia," Sarah Tettamanti, Ph.D., and colleagues describe a bispecific CAR-CIK strategy for AML that demonstrated the potential for improved efficacy and high specificity for CD123 and CD33 on leukemic cells while reducing the risk of life-threatening toxicities. In a poster titled, "Overexpression of CXCR4 Enhances the Efficacy of CAR-T Therapy for Acute Myeloid Leukemia," Marta Serafini, Ph.D., and colleagues found that combining the expression of CD33-CAR and CXCR4 improves in vivo CAR-CIK cell migration and retention within the bone marrow and subsequent AML eradication. In an AML mouse model, median survival improved with CXCR4 overexpression (p<0.0001). "Immunotherapies have the potential to allow the body to attack cancer cells with higher efficacy and improved safety when compared to traditional approaches to cancer treatment, but researchers have yet to advance the development of CAR-T cells to reach this full potential," said Charles Nicolette, Ph.D., Chief Executive Officer of CoImmune. "We are focused on advancing the science of immunotherapy with fundamentally new approaches as the only company developing gene-modified CAR-CIK cells. These new data demonstrate the potential for CAR-CIK cells to improve outcomes for B-ALL patients, while also opening the door to promising strategies that may increase the therapeutic potential in AML and solid tumor indications." About CoImmune, Inc. CoImmune is a privately held, clinical stage immuno-oncology company that will redefine cancer treatment using best-in-class cellular immunotherapies. Our allogeneic CAR-CIK technology platform for liquid and solid tumors is a variation on CAR-T therapy that promises enhanced efficacy with greatly reduced toxicity. Our autologous RNA-loaded dendritic cell technology for solid tumors uses amplified total tumor mRNA to program highly engineered dendritic cells to generate immune responses against neoantigens without the need to identify them. For more information visit . Investor Contact: Lori Harrelson Chief Financial Officer CoImmune, Inc. [email protected] Media Contact: Adam Daley Berry & Company Public Relations [email protected] 212-253-8881 SOURCE CoImmune, Inc.