Priming the Abscopal Effect Using Multifunctional Smart Radiotherapy Biomaterials Loaded with Immunoadjuvants

Abstract

In this study, we investigate the use of multifunctional smart radiotherapy biomaterials (SRBs) loaded with immunoadjuvants for boosting the abscopal effect of local radiotherapy (RT). SRBs were designed similar to currently used inert RT biomaterials, incorporating a biodegradable polymer with reservoir for loading payloads of the immunoadjuvant anti-CD40 monoclonal antibody. Lung (LLC1) tumors were generated both on the right and left flank of each mouse, with the left tumor representing metastasis. The mice were randomized and divided into eight cohorts with four cohorts receiving image-guided RT (IGRT) at 5 Gy and another similar four cohorts at 0 Gy. IGRT and Computed Tomography (CT) imaging were performed using a small animal radiation research platform (SARRP). Tumor volume measurements for both flank tumors and animal survival was assessed over 25 weeks. Tumor volume measurements showed significantly enhanced inhibition in growth for the right flank tumors of mice in the cohort treated with SRBs loaded with CD40 mAbs and IGRT. Results also suggest that the use of polymeric SRBs with CD40 mAbs without RT could generate an immune response, consistent with previous studies showing such response when using anti-CD40. Overall, 60% of mice treated with SRBs showed complete tumor regression during the observation period, compared to 10% for cohorts administered with anti-CD40 mAbs, but no SRB. Complete tumor regression was not observed in any other cohorts. The findings justify more studies varying RT doses and quantifying the immune-cell populations involved when using SRBs. Such SRBs could be developed to replace currently used RT biomaterials, allowing not only for geometric accuracy during RT, but also for extending RT to the treatment of metastatic lesions.

Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer

“…Interestingly, the use of anti-CD40 alone showed inhibition in tumor growth in the untreated tumor, but the primary tumor grew progressively and mice reached their end point in tumor size, following the IACUC approved protocol. The observed response in the untreated tumor has also been observed for other cancers with anti-CD40 administered in situ [16,17] and may be attributed to levels of immunosuppression in primary and metastatic tumor environments. To assess the abscopal effect, mice with two tumors were randomized into four different cohorts, including: control group, group treated with radiotherapy only, group treated with anti-CD40 only and the fourth group, treated with one fraction of radiotherapy and the immunoadjuvant anti-CD40.…”

“…Interestingly, the use of anti-CD40 alone showed inhibition in tumor growth in the untreated tumor, but the primary tumor grew progressively and mice reached their end point in tumor size, following the IACUC approved protocol. The observed response in the untreated tumor has also been observed for other cancers with anti-CD40 administered in situ [16,17] and may be attributed to levels of immunosuppression in primary and metastatic tumor environments.…”

“…Studies by the Formenti group have suggested that high doses of radiotherapy beyond 15 Gy lead to sub-optimal results in breast cancer [19]. Meanwhile, abscopal responses were also induced at lower single RT doses, e.g., in pancreatic cancer (5 Gy) [17] or lung cancer (6 Gy) [20]. As in previous studies, lower doses may be favorable to reduce immune-suppression.…”

“…A consensus from recent studies suggests the potential mechanism of the abscopal effect illustrated in Figure 5. The radiotherapy results in the release of neoantigens and damage-associated molecular patterns (DAMPs) lead to an increased infiltration of immune cells, mainly antigen presenting cells (APCs) [17]. Smilowitz et al have reported better treatment outcomes with higher RT doses (15-22.5 Gy), with an adjunct of immunotherapy in advanced intracerebral melanoma [18].…”

Delivery of Nanoparticle-Based Radiosensitizers for Radiotherapy Applications

“…They have been used as another medium for direct drug delivery inside the tumor volume [46,[98][99][100][101][102][103]. Similarly, smart radiotherapy biomaterials (e.g., NP-loaded spacers, fiducial markers, or hollow spacers loaded with NBRs) are made from biodegradable and bioerodible polymers loaded with NBRs for RT dose enhancement instead of current brachytherapy spacers, as shown Figures 1 and 5 [2,15,21,45,47,48,[104][105][106]. This requires no additional procedure since brachytherapy spacers and fiducial markers are routinely used in RT [15,45,48].…”