ImmunoGen (United States)

The advent of high-throughput data generation and artificial intelligence has transformed allergy research. Open-access database (OAD) and cohort-based database (CBD) provide essential resources for machine learning (ML)-driven algorithms for risk stratification and decision support. It is crucial for allergologists to understand their construction, strengths, and limitations. We review recently published databases with a focus on how these datasets can be combined to enhance research. OAD, including environmental monitoring resources, omics repositories, and electronic health records, offer scale, diversity, and opportunities for new hypotheses, but are often limited by sparse clinical annotation, heterogeneous data generation, and incomplete linkage to patient-level outcomes. CBD provide well-phenotyped patients, longitudinal follow up, and high-quality clinical and immunological measurements, yet face constraints in sample size, population diversity, and data sharing. Studies integrating OAD breadth with CBD label fidelity report improved predictive performance when paired with disciplined evaluation. Federated learning and portable feature specifications are emerging to enable privacy-preserving collaborations. Allergologists play a central role in building ML-ready resources. By ensuring rigorous clinical annotation, standardization of data, transparent methods, and independent validation, they can maximize the utility of OAD and CBD and their combination to accelerate progress toward precision allergy medicine.

TPS6585 Background: Despite improved outcomes with azacitidine (AZA) and venetoclax (VEN) in newly diagnosed (ND) unfit acute myeloid leukemia (AML), only a subset of patients (pts) respond (CR 37%; CR/CRi 66%) and long-term survival remains inadequate (mOS <15m, DiNardo NEJM 2020). The measurable residual disease (MRD)-negative rate was 41% in AZA-VEN treated pts in VIALE-A which was associated with improved survival (Pratz JCO 2022). CD123 is expressed on the majority of AML blasts and leukemic stem cells while minimally expressed on normal hematopoietic stem cells (Kovtun Blood Adv 2018). Pivekimab sunirine (PVEK, IMGN632) is an antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and an indolinobenzodiazepine pseudodimer (IGN) payload. The IGN payload alkylates DNA and causes single strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. Clinical data from the first 50 pts in the dose expansion cohorts 1 and 2 with ND AML demonstrated a 76% (22/29) MRD negativity rate (by flow cytometry, negativity threshold <0.1%) (Daver ASH 2023), supporting the continued enrollment of the PVEK+AZA+VEN triplet and further evaluation of the regimen’s antileukemia activity and safety in consideration of potential registration-enabling trials. Methods: This is an open-label, multicenter, phase 1b/2 study of PVEK administered in a combination with AZA+VEN in pts with ND CD123-positive (CD123+ by flow cytometry or IHC) AML, with no prior treatment with hypomethylating agents (HMA). Pts will receive the recommended phase 2 dose of PVEK 0.045 mg/kg IV as a < 30-minute outpatient infusion on day 7, AZA 75 mg/m2 SC or IV daily on days 1 to 7, and VEN 400 mg PO daily for up to 28 days in a 28-day cycle. During cycle 1, a bone marrow evaluation at or around day 21 is required to inform VEN dose duration. Current eligibility criteria for continued enrollment of AML patients unfit for intensive chemotherapy include age ≥ 75 years old, or age < 75 years old with ECOG 2-3, or at least one defined comorbidity. The primary study objectives are to assess antileukemia clinical activity (composite CR [complete remission] rate, overall response rate, duration of remission) and MRD-negativity rates. Key secondary objectives are safety and tolerability, pharmacokinetics and immunogenicity. The PVEK+AZA+VEN triplet in pts with ND unfit AML is currently enrolling across sites in France, Germany, Italy, Spain, UK and USA. Clinical trial information: NCT04086264 .

<div>Abstract<p><b>Purpose:</b> Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge.</p><p><b>Experimental Design:</b> The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti–glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line).</p><p><b>Results:</b> Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (<i>a</i>) increased numbers of CD8<sup>+</sup> T cells infiltrating tumor sites in anti-CTLA-4 mAb–treated mice and (<i>b</i>) increased cytokine secretion and Treg resistance of tumor-specific CD8<sup>+</sup> T cells with strongly upregulated CD25 expression in anti-GITR mAb–treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.</p><p><b>Conclusions:</b> This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic. Clin Cancer Res; 16(10); 2781–91. ©2010 AACR.</p></div>

<div>Abstract<p><b>Purpose:</b> Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge.</p><p><b>Experimental Design:</b> The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti–glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line).</p><p><b>Results:</b> Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (<i>a</i>) increased numbers of CD8<sup>+</sup> T cells infiltrating tumor sites in anti-CTLA-4 mAb–treated mice and (<i>b</i>) increased cytokine secretion and Treg resistance of tumor-specific CD8<sup>+</sup> T cells with strongly upregulated CD25 expression in anti-GITR mAb–treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.</p><p><b>Conclusions:</b> This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic. Clin Cancer Res; 16(10); 2781–91. ©2010 AACR.</p></div>