Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma

Aicher, Alexandra; Sindrilaru, Anca; Crişan, Diana; Thaiss, Wolfgang M.; Steinacker, J. M.; Beer, Meinrad; Wiegel, Thomas; Scharffetter‐­Kochanek, Karin; Beer, Ambros; Prasad, Vikas

doi:10.3390/pharmaceutics14071466

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…Impressive responses to combination peptide receptor radionuclide therapy (PRRT; 177 Lu-DOTATATE/DOTATOC) and ICIs in ICI-refractory metastatic Merkel cell carcinoma (mMCC), a skin cancer with occasional responses to PRRT, have been described in recent case reports [ 84 , 85 ]. In one report, a patient with mMCC with high metastatic burden who was resistant to avelumab and eventually progressed on ipilimumab/nivolumab, had a partial response to four additional doses of ipilimumab/nivolumab in combination with two cycles of 177 Lu-DOTATOC.…”

Section: Combination Trt and Immunotherapiesmentioning

confidence: 99%

“…In a second report, two patients with mMCC with primary resistance to avelumab received 6 cycles of 177 Lu-DOTATATE in combination with pembrolizumab. Both patients had PET/CT demonstrated responses at all disease sites for 3.6 and 4.8 months, respectively [ 84 ]. These exciting case reports have led to the announcement of a Phase II trial investigating 177 Lu-DOTATATE in combination with pembrolizumab in patients with MCC (NCT05583708).…”

Section: Combination Trt and Immunotherapiesmentioning

confidence: 99%

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Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

et al. 2022

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Targeted radionuclide therapy (TRT) and immunotherapy are rapidly growing classes of cancer treatments. Basic, translational, and clinical research are now investigating therapeutic combinations of these agents. In comparison to external beam radiation therapy (EBRT), TRT has the unique advantage of treating all disease sites following intravenous injection and selective tumor uptake and retention—a particularly beneficial property in metastatic disease settings. The therapeutic value of combining radiation therapy with immune checkpoint blockade to treat metastases has been demonstrated in preclinical studies, whereas results of clinical studies have been mixed. Several clinical trials combining TRT and immune checkpoint blockade have been initiated based on preclinical studies combining these with EBRT and/or TRT. Despite the interest in translation of TRT and immunotherapy combinations, many questions remain surrounding the mechanisms of interaction and the optimal approach to clinical implementation of these combinations. This review highlights the mechanisms of interaction between anti-tumor immunity and radiation therapy and the status of basic and translational research and clinical trials investigating combinations of TRT and immunotherapies.

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Section: Combination Trt and Immunotherapiesmentioning

confidence: 99%

Section: Combination Trt and Immunotherapiesmentioning

confidence: 99%

Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

et al. 2022

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Section: Incorporating Metabolic Imaging Into Trials Of Novel Immunot...mentioning

confidence: 99%

“…Further, combination therapies may introduce unique patterns of response and new toxicities, providing challenges for designing optimal treatment regimens [20]. For example, radiation exposure may increase neoantigenic presentation and has potential implications for the combination of radionuclide therapy with immune checkpoint inhibitors as an evolution of emerging theranostic paradigms with respect to administered activity and dosing intervals [21], but may also sensitize normal organs exposed to radiation to irAEs. Given increasing evidence of the importance of metabolic tumor volume [22], randomized clinical trials comparing treatment regimens should ideally be stratified and incorporation of [ 18 F]FDG PET/CT into therapeutic response assessment may yield earlier readouts of superior efficacy with a complete metabolic response having favorable prognostic implications even in patients with stable or partial radiologic responses.…”

Section: Incorporating Metabolic Imaging Into Trials Of Novel Immunot...mentioning

confidence: 99%

Perspectives on joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards for [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors

Lopci

Aide

Dimitrakopoulou-Strauß

et al. 2022

Cancer Imaging

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Response assessment in the context of immunomodulatory treatments represents a major challenge for the medical imaging community and requires a multidisciplinary approach with involvement of oncologists, radiologists, and nuclear medicine specialists. There is evolving evidence that [18F]FDG PET/CT is a useful diagnostic modality for this purpose. The clinical indications for, and the principal aspects of its standardization in this context have been detailed in the recently published “Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0”. These recommendations arose from a fruitful collaboration between international nuclear medicine societies and experts in cancer treatment. In this perspective, the key elements of the initiative are reported, summarizing the core aspects of the guidelines for radiologists and nuclear medicine physicians. Beyond the previous guidelines, this perspective adds further commentary on how this technology can advance development of novel therapeutic approaches and guide management of individual patients.

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“…Combining TRT with potentially synergistic agents (chemotherapy, immune checkpoint inhibitors, PARP inhibitors, etc.) or with other radiopharmaceuticals is being evaluated in ongoing clinical trials (14)(15)(16)(17). The focus of this paper is to describe and explore a novel technology platform that may improve the therapeutic effect of TRT by combining two radionuclides from the same decay chain; one TAT component targeting the stromal elements of osteoblastic skeletal metastases and the other by selective cell-surface binding to cancer cells in extraskeletal and skeletal metastases.…”

Section: Introductionmentioning

confidence: 99%

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

Juzeniene

Stenberg²,

Bruland³

et al. 2023

Front. Med.

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Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution. We hypothesize that the dual targeting solution containing bone-seeking 224Ra and cell-directed complexes of progeny 212Pb is a promising approach to treat metastatic cancers with bone and soft tissue lesions as well as skeletal metastases of mixed lytic/osteoblastic nature. A novel liquid 224Ra/212Pb-generator for rapid preparation of a dual targeting solution is described. Cancer cell targeting monoclonal antibodies, their fragments, synthetic proteins or peptides can all be radiolabeled with 212Pb in the 224Ra-solution in transient equilibrium with daughter nuclides. Thus, 224Ra targets stromal elements in sclerotic bone metastases and 212Pb-chelated-conjugate targets tumor cells of metastatic prostate cancer or osteosarcoma. The dual targeting solution may also be explored to treat metastatic breast cancer or multiple myeloma after manipulation of bone metastases to a more osteoblastic phenotype by the use of bisphosphonates, denosumab, bortezomib or hormone therapy prior to treatment. This may improve targeting of bone-seeking 224Ra and render an augmented radiation dose deposited within metastases. Our preliminary preclinical studies provide conceptual evidence that the dual 224Ra-solution with bone or tumor-targeted delivery of 212Pb has potential to inhibit cancer metastases without significant toxicity. In some settings, the use of a booster dose of purified 212Pb-conjugate alone could be required to elevate the effect of this tumor cell directed component, if needed, e.g., in a fractionated treatment regimen, where the dual targeting solution will act as maintenance treatment.

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Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma

Cited by 10 publications

References 40 publications

Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

Developments in Combining Targeted Radionuclide Therapies and Immunotherapies for Cancer Treatment

Perspectives on joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards for [18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors

Dual targeting with 224Ra/212Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach

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