John Violet: radiation oncologist and physician scientist who pioneered targeted radionuclide therapy for prostate cancer

BackgroundWhile checkpoint blockade has been unsuccessful in prostate cancer trials, the approval of Sipuleucel-T demonstrates the value of antigen-specific vaccination approaches for this disease. We have studied a DNA vaccine specific for the ligand-binding domain of the androgen receptor (pTVG-AR) as a more scalable vaccination approach, though its efficacy is likely limited by the immunosuppressive prostate microenvironment. External beam radiotherapy has been shown to sensitize poorly responsive tumors to immunotherapy, but is infeasible for patients with widely metastatic disease. Our group has developed a compound called NM600 that can deliver radiation to all cancer sites simultaneously, similar to other targeted radionuclide therapy (TRT) approaches. In this study, we used TRT in combination with pTVG-AR to improve anti-tumor efficacy in a murine prostate cancer model.Methods6-week old male C57BL/6 mice were implanted subcutaneously with TRAMP-C1 cells. pTVG-AR or the empty vector were administered weekly from the day after tumor implantation. An intravenous injection was administered of 50 (”low-dose”) or 250 μCi (”high dose”) of 90Y-NM600, estimated to deliver a dose of 3.1 Gy or 15.5 Gy to 300 mm3 tumors, respectively. In one study, this TRT treatment was repeated once after three weeks. Groups of mice (n=5) were euthanized at several time points for flow cytometry analysis of the tumors. Separate cohorts (n=7) were followed for survival.ResultsLow-dose TRT administered once in combination with pTVG-AR (median survival 91 days) significantly improved survival more than low-dose TRT alone (median survival 59 days; p=.049) or pTVG-AR alone (median survival 59 days; p=0.01). Low-dose TRT plus pTVG-AR was also superior to high-dose TRT plus pTVG-AR (median survival 67 days; p=0.05). We next examined the effect of giving high-dose TRT twice in combination pTVG-AR. We found that the combination of fractionated TRT and pTVG-AR greatly slowed tumor growth unlike fractionated TRT alone (p=0.03). High-dose TRT + pTVG-AR caused a two-fold increase in CD86 expression on dendritic cells (p=0.0009) on Day 3 and a 10% increase in effector memory CD8+ T cells (p=0.002) on Day 1 compared to TRT alone. This combination also resulted in T cells with 3-fold lower PD-1 expression (p=4e-7) and 2-fold lower TIGIT expression (p=0.01).ConclusionsThese data suggest that the combination of antigen-specific vaccination and TRT can be an effective treatment for cancers that are refractory to immunotherapy. This combination may act through increasing co-stimulation by dendritic cells, leading to a more active cytolytic CD8+ T cell population.

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Targeted Radionuclide Therapy of Prostate Cancer

Therapeutic Nuclear Medicine - Medical Radiology ◽

10.1007/174_2012_786 ◽

2013 ◽

pp. 617-628

Author(s):

Stanley J. Goldsmith ◽

Scott T. Tagawa ◽

Shankar Vallabhajosula ◽

Anastasia Nikolopoulou ◽

Irina Lipai ◽

...

Keyword(s):

Prostate Cancer ◽

Radionuclide Therapy ◽

Targeted Radionuclide Therapy

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Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-019-04345-0 ◽

2019 ◽

Vol 46 (9) ◽

pp. 1919-1930 ◽

Cited By ~ 20

Author(s):

Cristina Müller ◽

Christoph A. Umbricht ◽

Nadezda Gracheva ◽

Viviane J. Tschan ◽

Giovanni Pellegrini ◽

...

Keyword(s):

Prostate Cancer ◽

Radionuclide Therapy ◽

Targeted Radionuclide Therapy

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Molecular Imaging and Targeted Radionuclide Therapy of Prostate Cancer

Journal of Nuclear Medicine ◽

10.2967/jnumed.116.175497 ◽

2016 ◽

Vol 57 (Supplement_3) ◽

pp. 3S-5S ◽

Cited By ~ 4

Author(s):

W. A. Weber ◽

M. J. Morris

Keyword(s):

Prostate Cancer ◽

Molecular Imaging ◽

Radionuclide Therapy ◽

Targeted Radionuclide Therapy

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629P Patient-reported outcomes in prostate cancer patients receiving PSMA-targeted radionuclide therapy

Annals of Oncology ◽

10.1016/j.annonc.2021.08.1142 ◽

2021 ◽

Vol 32 ◽

pp. S663-S664

Author(s):

B.D. Gonzalez ◽

M.I. Sun ◽

C. Thomas ◽

S. Eisel ◽

L. Oswald ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Patients ◽

Radionuclide Therapy ◽

Patient Reported Outcomes ◽

Targeted Radionuclide Therapy ◽

Patient Reported

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Combination Therapy, a Promising Approach to Enhance the Efficacy of Radionuclide and Targeted Radionuclide Therapy of Prostate and Breast Cancer

Pharmaceutics ◽

10.3390/pharmaceutics13050674 ◽

2021 ◽

Vol 13 (5) ◽

pp. 674

Author(s):

Tyrillshall S. T. Damiana ◽

Simone U. Dalm

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Radionuclide Therapy ◽

Complete Response ◽

External Beam Radiation ◽

Cancer Therapies ◽

Targeted Radionuclide Therapy ◽

Beam Radiation ◽

Cancer Types ◽

Preclinical And Clinical Studies

In recent years, radionuclide therapy (RT) and targeted radionuclide therapy (TRT) have gained great interest in cancer treatment. This is due to promising results obtained in both preclinical and clinical studies. However, a complete response is achieved in only a small percentage of patients that receive RT or TRT. As a consequence, there have been several strategies to improve RT and TRT outcomes including the combination of these treatments with other well-established anti-cancer therapies, for example, chemotherapy. Combinations of RT and TRT with other therapies with distinct mechanisms of action represent a promising strategy. As for prostate cancer and breast cancer, the two most prevalent cancer types worldwide, several combination-based therapies have been evaluated. In this review, we will provide an overview of the RT and TRT agents currently used or being investigated in combination with hormone therapy, chemotherapy, immunotherapy, and external beam radiation therapy for the treatment of prostate cancer and breast cancer.

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