163 research outputs found
Tumor-targeted and immune-targeted monoclonal antibodies: Going from passive to active immunotherapy
No full textMonoclonal antibodies (mAbs) have inaugurated the concepts of tumor-targeted therapy and personalized medicine. A new family of mAbs is currently emerging in the clinic, which target immune cells rather than cancer cells. These immune-targeted therapies have recently demonstrated long-term tumor responses in adults with refractory/relapsing metastatic solid tumors. Pediatric cancers are different from their adult counterparts in terms of histological features and immune infiltrates. However, the same immune checkpoint targets can be expressed within the microenvironment of pediatric tumors. The benefits of immune checkpoint blockade in pediatric cancers are currently under evaluation in early phase clinical trials
Immunotherapy for Pediatric Malignancies
No full textThis book provides a comprehensive overview of current immunotherapy strategies, and how these may be applicable to childhood cancers. The first part of the book reviews how the immune system recognizes cancer, and the various escape mechanisms allowing tumour growth. The importance of the tumor microenvironment and the challenges this may present to achieving effective immunotherapy are discussed. Monoclonal antibodies, cellular, cytokine and vaccine therapies are all comprehensively reviewed, with particular focus on their potential application to pediatric cancers. Practical aspects of delivering such therapies to children, likely toxicities and potential biomarkers are considered. Finally, consideration is given to how, in the longer term, such therapies may be combined with conventional therapies such as chemotherapy and radiotherapy
Abstract 2466: Sequential tumor and immune targeted immunotherapy: Anti-tumor activity of antibody drug conjugate Trastuzumab Emtansine (T-DM1) with CD137 stimulation in HER-2+ breast cancer therapy
No full textInternational audienceThe mainstay of HER2+ breast cancer treatment has been monoclonal antibody therapy with Trastuzumab, a humanized antibody that targets HER-2. However, the efficacy of Trastuzumab monotherapy is only 10-15%. Therefore, strategies are being developed to enhance its therapeutic efficacy. Our previous study demonstrated that stimulation of NK cells with an anti-CD137 agonistic mAb enhanced Trastuzumab-mediated Antibody Dependent Cellular Cytotoxicity (ADCC). Anti-CD137 agonistic mAb enhanced anti-breast cancer activity of Trastuzumab in vivo in a xenotransplanted human breast cancer model (Kohrt et al. J Clin. Invest, 2012, 22:3). We have developed a treatment regimen consisting of sequential administration of Trastuzumab followed by CD137 antibody as three weekly injections. This regimen demonstrated more potent antitumor activity than administration of anti-CD137 mAb followed by Trastuzumab. Our combination therapy was superior to Traztuzumab alone in a primary HER2-overexpressing-breast tumor xenotransplant model but was ineffective in low HER-2 expressing breast cancer model. Next, we evaluated the therapeutic efficacy of FDA approved antibody drug conjugate Trastuzumab Emtansine (T-DM1) in combination with CD137 antibody. We used HER2 over-expressing HER18 xenograft model and an SU-258 primary breast cancer model in our studies. Following tumor inoculation, mice received either T-DM1 on day 3 (for HER18 xenograft), or day 30 (for SU-258) and anti-CD137 antibody on day 4(or HER18) or day 31(for SU-258) with each treatment repeated weekly for a total of three weeks. Sequential antibody strategy with T-DM1 and CD137 significantly improved survival compared to T-DM1 alone or with Trastuzumab and CD137 antibody. Our results demonstrate that T-DM1 retains its potency and demonstrates synergistic activity with anti-CD137 mAb therapy against HER2-overexpressing breast cancer models. Our results support a novel, sequential antibody approach against HER-2+breast cancer, by targeting first the tumor with an antibody drug conjugate and then the host immune system. Clinical investigations are now planned to determine the clinical outcome of our immunotherapy strategy. Citation Format: Suparna Dutt, Narendiran Rajasekaran, Aurelien Marabelle, Roch Houot, Mohith Sadaram, Jonathan Hebb, Idit Sagiv-Barfi, Sid Ambulkar, Amanda Rajapaksa, Cariad Chester, Erin Waller, Holbrook Kohrt. Sequential tumor and immune targeted immunotherapy: Anti-tumor activity of antibody drug conjugate Trastuzumab Emtansine (T-DM1) with CD137 stimulation in HER-2+ breast cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2466. doi:10.1158/1538-7445.AM2015-246
Pembrolizumab in Patients With Microsatellite Instability–High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study
No full textPURPOSE Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability–high or mismatch repair–deficient (MSI-H/dMMR) tumors, including endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158. METHODS Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. RESULTS As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received 26 weeks of follow-up; N 5 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.71 months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had $ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7%; no fatal events). CONCLUSION Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer. © 2022 by American Society of Clinical Oncology
Abstract IA25: Local immunomodulation at a single site of tumor generates a therapeutic immune response that cures metastatic disease at distant sites, including the brain.
No full textAbstract CT034: Activation of the antitumor immune response of gamma9delta2 T cells in patients with solid or hematologic malignancies with ICT01, a first-in-class, monoclonal antibody targeting butyrophilin 3A: The EVICTION study
No full textInternational audienceAbstract Background: Gamma9 Delta2 (γ9δ2) T cells function at the crossroad of innate and adaptive immunity with important roles in immune responses against pathogens and carcinogenesis, making them an attractive target for cancer immunotherapy. Butyrophilin (BTN) 3A (CD277) is an immune checkpoint molecule expressed on tumors and cells of the immune system that is required for γ9δ2 T cell activation. These observations led to the design and development of ICT01, a humanized, monoclonal antibody that binds the extracellular domain of all 3 isoforms of BTN3A1/A2/A3 and induces pAg-independent γ9δ2 T cell activation and killing of multiple tumors in nonclinical settings. Methods: EVICTION (www.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31) is a first-in-human, open-label clinical study to assess the safety, tolerability, and activity of a range of IV doses of ICT01 as monotherapy and in combination with pembrolizumab, in patients with advanced-stage, relapsed/refractory cancer. Following Regulatory and Ethics Committee approvals, the study is being conducted at cancer centers in France, Belgium, Spain, Germany, the UK and USA. Following signed informed consent, patients received ICT01 every 3 weeks with blood samples collected at multiple timepoints for immunophenotyping by flow cytometry and cytokine analysis (IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13). Tumor biopsies are collected at baseline and on Day 28 for immunohistochemistry (e.g., BTN3A, γ9δ2 T cells) and expression profiling of cancer- and immunity-related genes. Results: Solid tumor (ST) dose cohorts 1-4 (total n=20) were enrolled and treated with ICT01 doses ranging from 20 μg to 20 mg, and dose cohort 1 of hematologic cancer patients (n=3, 200 μg) has been enrolled. ICT01 was well-tolerated, with no dose-limiting toxicities or related SAEs reported. Target occupancy on T cells at 30 min or 4 hours post first dose ranged from 34% (700 μg, n=2), 79% (2 mg, n=5), 93% (7 mg, n=4) and 100% (20 mg, n=1), with activated γ9δ2 T cells (CD69+) migrating from the blood within 30 min of dosing that led to a > 95% decrease from baseline in the number of circulating γ9δ2 T cells for all 4 doses by 24hrs. The 2nd dose of ICT01 induced a similar activation & migration of γ9δ2 T cells from the circulation. There were no effects on CD4/CD8 T cells, NK, or B cells. Available cytokine data from ST cohorts 1 & 2 showed no CRS although transient 2-3x increases in IFNγ, TNFα, & IL-2 were observed 4 hours post dose in patients with higher baseline γ9δ2 T cell counts. A 5-10x increase of IFNγ was observed on Days 7 & 28 in ST cohort 2, consistent with γ9δ2 T cell activation. Digital pathology analysis of tumor biopsies of a cohort 1 melanoma pt demonstrated a 25x and 8x increase of CD3-TCRgamma delta++ and CD3+ cell densities, respectively, as compared to baseline. Analyses of additional cohorts are ongoing and will be presented. Conclusion: The preliminary results demonstrate that ICT01 safely and potently activates the anti-tumor immune response of γ9δ2 T cells mediated by BTN3A. Citation Format: Aurelien Marabelle, Christiane Jungels, Johann De Bono, Norbert Vey, Martin Wermke, Elena Garralda, Steven Le Gouill, Patricia LoRusso, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iche, Daniel Olive, Paul A. Frohna. Activation of the antitumor immune response of gamma9delta2 T cells in patients with solid or hematologic malignancies with ICT01, a first-in-class, monoclonal antibody targeting butyrophilin 3A: The EVICTION study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT034
Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer
No full textPOLD1 mutations; Immune checkpoint inhibitors; Metastatic colorectal cancerMutaciones POLD1; Inhibidores de puntos de control inmunológico; Cáncer colorrectal metastásicoMutacions POLD1; Inhibidors de punts de control immunològic; Càncer colorectal metastàticBackground
POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.
Patients and methods
In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/− anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures.
Results
POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature.
Conclusions
Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.This research was partially funded by Italian Ministry of Health “Ricerca Corrente” funds, and supported by: Nuovo Soldati foundation, MSKCC T32-CA009512, Molecular Cytology Core Grant [grant number P30 CA008748], Swim Across America, Dalton Family Foundation. The sequencing of tumors of the AcSé clinical trial (TMB) was part of an ancillary analysis program of Acsé Nivolumab (Acsé Cible) funded by a research grant from the Ligue contre le Cancer and has been previously published (Rousseau et al, Cancer Discovery 2022)
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