Interim evaluation of a targeted radiotherapeutic, CLR 131, in relapsed/refractory diffuse large B-cell lymphoma patients (R/R DLBCL)

Longcor, Jarrod; Oliver, Kate; Friend, John; Callandar, Natalie

doi:10.1093/annonc/mdz251

Cited by 2 publications

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“…29 First generation 131 I-NM404 is currently being investigated as a treatment for metastatic multiple myeloma and other cancers. [30][31][32][33] We have recently focused on evaluating the second generation APC, NM600, which can be radiolabeled with a variety of radiometals. By labeling with 86 Y, we can image tumors and perform dosimetry estimation via PET/CT, while by labeling with the isotopic pair, 90 Y, we are able to deliver therapeutic radiation.…”

Section: Open Accessmentioning

confidence: 99%

Antitumor efficacy of⁹⁰Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

Potluri

Ferreira

Grudzinski

et al. 2022

J Immunother Cancer

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BackgroundSystemic radiation treatments that preferentially irradiate cancer cells over normal tissue, known as targeted radionuclide therapy (TRT), have shown significant potential for treating metastatic prostate cancer. Preclinical studies have demonstrated the ability of external beam radiation therapy (EBRT) to sensitize tumors to T cell checkpoint blockade. Combining TRT approaches with immunotherapy may be more feasible than combining with EBRT to treat widely metastatic disease, however the effects of TRT on the prostate tumor microenvironment alone and in combinfation with checkpoint blockade have not yet been studied.MethodsC57BL/6 mice-bearing TRAMP-C1 tumors and FVB/NJ mice-bearing Myc-CaP tumors were treated with a single intravenous administration of either low-dose or high-dose 90Y-NM600 TRT, and with or without anti-PD-1 therapy. Groups of mice were followed for tumor growth while others were used for tissue collection and immunophenotyping of the tumors via flow cytometry.Results90Y-NM600 TRT was safe at doses that elicited a moderate antitumor response. TRT had multiple effects on the tumor microenvironment including increasing CD8 +T cell infiltration, increasing checkpoint molecule expression on CD8 +T cells, and increasing PD-L1 expression on myeloid cells. However, PD-1 blockade with TRT treatment did not improve antitumor efficacy. Tregs remained functional up to 1 week following TRT, but CD8 +T cells were not, and the suppressive function of Tregs increased when anti-PD-1 was present in in vitro studies. The combination of anti-PD-1 and TRT was only effective in vivo when Tregs were depleted.ConclusionsOur data suggest that the combination of 90Y-NM600 TRT and PD-1 blockade therapy is ineffective in these prostate cancer models due to the activating effect of anti-PD-1 on Tregs. This finding underscores the importance of thorough understanding of the effects of TRT and immunotherapy combinations on the tumor immune microenvironment prior to clinical investigation.

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Section: Open Accessmentioning

confidence: 99%

Antitumor efficacy of⁹⁰Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

Potluri

Ferreira

Grudzinski

et al. 2022

J Immunother Cancer

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“…Following the results of the DREAMM-1 and two trials, multiple studies concerning belantamab mafodotin are currently in the pipelines, with several of these studies actively recruiting patients ( Table 3 ). The focuses of these upcoming trials include the efficacy and safety of belamaf in comparison to pomalidomide plus low-dose dexamethasone (DREAMM-3), belamaf in combination with pembrolizumab (DREAMM-4), and belamaf in combination with lenalidomide or bortezomib plus dexamethasone (DREAMM-6) [ 93 , 94 , 95 ]. The DREAMM-5 trial aims to analyze the efficacy of belamaf plus various anti-cancer drugs, including GSK335609 (inducible T-cell costimulatory agonist), nirogacestat (gamma secretase inhibitor), and GSK317498 (selective OX40 agonist) [ 96 , 97 , 98 ].…”

Section: Clinical Studies: Safety and Efficacymentioning

confidence: 99%

Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

et al. 2021

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Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have previously attempted four other treatments, including an anti-CD38 monoclonal antibody, a proteosome inhibitor, and an immunomodulatory agent. In November 2017, the FDA designated belamaf as a breakthrough therapy for heavily pretreated patients with relapsed/refractory multiple myeloma. In August 2020, the FDA granted accelerated approval as a monotherapy for relapsed or treatment-refractory multiple myeloma. The drug was also approved in the EU for this indication in late August 2020. Of note, belamaf is associated with the following adverse events: decreased platelets, corneal disease, decreased or blurred vision, anemia, infusion-related reactions, pyrexia, and fetal risk, among others. Further studies are necessary to evaluate efficacy in comparison to other standard treatment modalities and as future drugs in this class are developed.

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Interim evaluation of a targeted radiotherapeutic, CLR 131, in relapsed/refractory diffuse large B-cell lymphoma patients (R/R DLBCL)

Cited by 2 publications

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Antitumor efficacy of⁹⁰Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

Antitumor efficacy of⁹⁰Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

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Interim evaluation of a targeted radiotherapeutic, CLR 131, in relapsed/refractory diffuse large B-cell lymphoma patients (R/R DLBCL)

Cited by 2 publications

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Antitumor efficacy of90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

Antitumor efficacy of90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

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Antitumor efficacy of⁹⁰Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors

Antitumor efficacy of⁹⁰Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors