Beyond checkpoint inhibition – Immunotherapeutical strategies in combination with radiation

Eckert, Franziska; Gaipl, Udo S.; Niedermann, Gabriele; Hettich, Michael; Schilbach, Karin; Huber, Stephan M.; Zips, Daniel

doi:10.1016/j.ctro.2016.12.006

Cited by 28 publications

(22 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its up-regulated expression had already been described as an unwanted effect of ionizing radiation [62]. In order to counteract immunosuppressive effects and exploit the immune-activating properties of the studied combination, immune checkpoint inhibitors can be used [62][63][64][65]. The approved antibodies anti-PD-L1 nivolumab and pembrolizumab were shown to have positive effects in melanoma treatment [66].…”

Section: Discussionmentioning

confidence: 99%

Combination of Gas Plasma and Radiotherapy Has Immunostimulatory Potential and Additive Toxicity in Murine Melanoma Cells in Vitro

Pasqual-Melo

Sagwal

Freund

et al. 2020

IJMS

View full text Add to dashboard Cite

Despite continuous advances in therapy, malignant melanoma is still among the deadliest types of cancer. At the same time, owing to its high plasticity and immunogenicity, melanoma is regarded as a model tumor entity when testing new treatment approaches. Cold physical plasma is a novel anticancer tool that utilizes a plethora of reactive oxygen species (ROS) being deposited on the target cells and tissues. To test whether plasma treatment would enhance the toxicity of an established antitumor therapy, ionizing radiation, we combined both physical treatment modalities targeting B16F10 murine melanoma cell in vitro. Repeated rather than single radiotherapy, in combination with gas plasma-introduced ROS, induced apoptosis and cell cycle arrest in an additive fashion. In tendency, gas plasma treatment sensitized the cells to subsequent radiotherapy rather than the other way around. This was concomitant with increased levels of TNFα, IL6, and GM-CSF in supernatants. Murine JAWS dendritic cells cultured in these supernatants showed an increased expression of cell surface activation markers, such as MHCII and CD83. For PD-L1 and PD-L2, increased expression was observed. Our results are the first to suggest an additive therapeutic effect of gas plasma and radiotherapy, and translational tumor models are needed to develop this concept further.

show abstract

Section: Discussionmentioning

confidence: 99%

Combination of Gas Plasma and Radiotherapy Has Immunostimulatory Potential and Additive Toxicity in Murine Melanoma Cells in Vitro

Pasqual-Melo

Sagwal

Freund

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…[7][8][9][10] However, these effects are weak and rare with RT alone, and combination with immunotherapies might induce stronger adaptive immune responses. [11][12][13] Hence, the combination of RT with different immunotherapeutic strategies is being explored, including for prostate cancer. 8,10 Preclinical models as well as clinical observations reported better local control as well as abscopal effects compared to monotherapies.…”

Section: Introductionmentioning

confidence: 99%

Impact of curative radiotherapy on the immune status of patients with localized prostate cancer

et al. 2018

View full text Add to dashboard Cite

Combination of radiotherapy with immunotherapy has become an attractive concept for the treatment of cancer. The objective of this study was to assess the effect of curative, normofractionated radiotherapy on peripheral immune lymphocytes in prostate cancer patients, in order to propose a rationale for scheduling of normofractionated radiotherapy with T-cell based immunotherapy. In a prospective study (clinicaltrials.gov: NCT01376674), eighteen patients with localized prostate cancer were treated with radiotherapy with or without hormonal therapy. Irradiation volumes encompassed prostate and, in select cases, elective pelvic nodal regions. Blood samples were collected from all patients before, during, and after radiotherapy, as well as from 6 healthy individuals as control. Normofractionated radiotherapy of prostate cancer over eight weeks had a significant influence on the systemic immune status of patients compared to healthy controls. Absolute leukocyte and lymphocyte counts decreased during treatment as did peripheral blood immune subsets (T cells, CD8 + and naïve CD4 + T cells, B cells). Regulatory T cells and NK cells increased. Proliferation of all immune cells except regulatory T cells increased during RT. Most of these changes were transient. Importantly, the functionality of T lymphocytes and the frequency of antigen-specific CD8 + T cells were not affected during therapy. Our data indicate that combination of normofractionated radiotherapy with immunotherapy might be feasible for patients with prostate cancer. Conceptually, beginning with immunotherapy early during the course of radiotherapy could be beneficial, as the percentage of T cells is highest, the percentage of regulatory T cells is lowest, and as the effects of radiotherapy did not completely subside 3 months after end of radiotherapy.

show abstract

“…Local radiation of solid tumor lesions during PET imaging might also be supportive for UniCAR T cell immunotherapy as ionizing radiation can increase CAR T cell infiltrations, for example, by triggering the up-regulation of certain tumor antigens, adhesion molecules and the release of T cell attracting chemokines. 56,57 In addition, an increased PSMA expression following androgen deprivation therapy was reported 58 and is thus an attractive starting point for further therapy combinations with PSMA PLT-TM theranostics.…”

Section: Discussionmentioning

confidence: 96%

A theranostic PSMA ligand for PET imaging and retargeting of T cells expressing the universal chimeric antigen receptor UniCAR

et al. 2019

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T cells have shown impressive therapeutic potential. Due to the lack of direct control mechanisms, therapy-related adverse reactions including cytokine release-and tumor lysis syndrome can even become life-threatening. In case of target antigen expression on non-malignant cells, CAR T cells can also attack healthy tissues. To overcome such side effects, we have established a modular CAR platform termed UniCAR: UniCAR T cells per se are inert as they recognize a peptide epitope (UniCAR epitope) that is not accessible on the surface of living cells. Bifunctional adapter molecules termed target modules (TM) can cross-link UniCAR T cells with target cells. In the absence of TMs, UniCAR T cells automatically turn off. Until now, all UniCAR TMs were constructed by fusion of the UniCAR epitope to an antibody domain. To open up the wide field of low-molecular-weight compounds for retargeting of UniCAR T cells to tumor cells, and to follow in parallel the progress of UniCAR T cell therapy by PET imaging we challenged the idea to convert a PET tracer into a UniCAR-TM. For proof of concept, we selected the clinically used PET tracer PSMA-11, which binds to the prostatespecific membrane antigen overexpressed in prostate carcinoma. Here we show that fusion of the UniCAR epitope to PSMA-11 results in a low-molecular-weight theranostic compound that can be used for both retargeting of UniCAR T cells to tumor cells, and for non-invasive PET imaging and thus represents a member of a novel class of theranostics.

show abstract

Beyond checkpoint inhibition – Immunotherapeutical strategies in combination with radiation

Cited by 28 publications

References 123 publications

Combination of Gas Plasma and Radiotherapy Has Immunostimulatory Potential and Additive Toxicity in Murine Melanoma Cells in Vitro

Combination of Gas Plasma and Radiotherapy Has Immunostimulatory Potential and Additive Toxicity in Murine Melanoma Cells in Vitro

Impact of curative radiotherapy on the immune status of patients with localized prostate cancer

A theranostic PSMA ligand for PET imaging and retargeting of T cells expressing the universal chimeric antigen receptor UniCAR

Contact Info

Product

Resources

About