Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response

Domankevich, Vered; Cohen, Akiba A.; Efrati, Margalit; Schmidt, Michael; Rammensee, Hans‐Georg; Nair, Sujit S.; Tewari, Ashutosh; Kelson, I.; Keisari, Yona

doi:10.1007/s00262-019-02418-5

Cited by 31 publications

(32 citation statements)

References 33 publications

(31 reference statements)

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“…How best can TLR9 agonists be combined with RT, and possibly newer modalities including alpha-emitters? 208 Ongoing clinical trials will help to answer some questions while elucidating biomarkers of resistance and response with the eventual goal of broadening the use of TLR9 agonists in solid tumors.…”

Section: Discussionmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

102

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Toll-like receptor 9 (TLR9) is a pattern recognition receptor that is predominantly located intracellularly in immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APC). The primary ligands for TLR9 receptors are unmethylated cytidine phosphate guanosine (CpG) oligodinucleotides (ODN). TLR9 agonists induce inflammatory processes that result in the enhanced uptake and killing of microorganisms and cancer cells as well as the generation of adaptive immune responses. Preclinical studies of TLR9 agonists suggested efficacy both as monotherapy and in combination with several agents, which led to clinical trials in patients with advanced cancer. In these studies, intravenous, intratumoral, and subcutaneous routes of administration have been tested; with anti-tumor responses in both treated and untreated metastatic sites. TLR9 agonist monotherapy is safe, although efficacy is minimal in advanced cancer patients; conversely, combinations appear to be more promising. Several ongoing phase I and II clinical trials are evaluating TLR9 agonists in combination with a variety of agents including chemotherapy, radiotherapy, targeted therapy, and immunotherapy agents. In this review article, we describe the distribution, structure and signaling of TLR9; discuss the results of preclinical studies of TLR9 agonists; and review ongoing clinical trials of TLR9 agonists singly and in combination in patients with advanced solid tumors.

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Section: Discussionmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

102

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“…Another interesting partner for combination with TAT could be DaRT, 224 Ra-based brachytherapy [118,119]. DaRT was shown to be of great potential in a localized tumor treatment in both pre-clinical and clinical studies, such as in breast, colon, skin, and squamous head and neck cancer [120][121][122]. Combining this approach with TAT could lead to a synergetic effect, as well as to the selective destruction of tumors and their metastases while minimizing side effects.…”

Section: Discussionmentioning

confidence: 99%

Atomic Nanogenerators in Targeted Alpha Therapies: Curie’s Legacy in Modern Cancer Management

2020

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Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic cancer diseases. This is due to their peculiar physical, chemical, and biological characteristics, leading to astonishing responses in otherwise resistant patients. Nevertheless, there are still a few obstacles and hurdles to be overcome that hamper the broader utilization in the clinical setting. Next to the limited supply and relatively high costs, the in vivo complex stability and the fate of the recoiling daughter radionuclides are substantial problems that need to be solved. In radiobiology, the mechanisms underlying treatment efficiency, possible resistance mechanisms, and late side effect occurrence are still far from being understood and need to be unraveled. In this review, the current knowledge on the scientific and clinical background of targeted alpha therapies is summarized. Furthermore, open issues and novel approaches with a focus on the future perspective are discussed. Once these are unraveled, targeted alpha therapies with atomic in vivo nanogenerators can be tailored to suit the needs of each patient when applying careful risk stratification and combination therapies. They have the potential to become one of the major treatment pillars in modern cancer management.

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“…Some strategies such as combining a therapy with immunomodulators were tested for promoting complete tumor regression in vivo animals models and, higher inhibition on tumor growth was obtained in the animals treated with immunomodulators before a therapy than a therapy alone. 171 Major strategies in targeted a therapy for limiting nuclear recoil effect can be performed by the use of single a particle emitters and/or carriers that are able to stop the spreading of recoils labeled with a emitter and the use of carriers providing controlled release of a particle emitters that is called the DaRT concept. 32 In addition, more accurate and target-specific cancer therapy can also be achieved by the application of different delivery systems apart from peptides, small molecules, mAb, and mAb fragments for targeted a therapy.…”

Section: Conclusion and New Directionsmentioning

confidence: 99%

Targeted Alpha Therapy and Nanocarrier Approach

Silindir-Gunay

Karpuz

Özer

2020

Cancer Biotherapy and Radiopharmaceuticals

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The rates of cancer incidence and mortality are increasing day by day. Although several conventional methods including surgery, chemotherapy, and radiotherapy (RT) exist for cancer treatment, they are insufficient in the eradication of all tumor tissues and have some side-effects such as narrow therapeutic index and serious sideeffects to healthy tissues. Moreover, it may probably recur in time due to the survival and spreading of cancerous cells or any possible metastases. Targeted radionuclide therapy is a promising alternative. a particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon emission of a particles, the daughter nuclides induce a recoil energy to lead decoupling from any chemical bond that may accumulate in normal tissues. Targeted a therapy can also be performed by targeted delivery systems apart from mAb, mAb fragments, peptides, and small molecules for selective tumor therapy. Targeted drug delivery systems have been developed to overcome the limitations of a therapy. Moreover, drug delivery systems are one of the most searched applications in cancer imaging and/or treatment due to their targeting ability to tumor or biocompatibility properties. The aim of this article is to summarize tumor therapy applications, targeted a RT approach, and to review the role of drug delivery systems in the delivery of a particles for cancer therapy and some instances of targeted a-emitting drug delivery systems from the literature.

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Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response

Cited by 31 publications

References 33 publications

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Atomic Nanogenerators in Targeted Alpha Therapies: Curie’s Legacy in Modern Cancer Management

Targeted Alpha Therapy and Nanocarrier Approach

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