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The recent FDA approvals of immunomodulatory drugs such as Nivoluvamab (Opdivo), Pembrolizumab (Keytruda) and Ipilimumab (Yervoy) for treatment of Non-small cell lung cancer (NSCLC) and melanoma have renewed interest in cancer immunotherapy. Initial attempts to activate the immune system to improve anti-tumor immunity by vaccination and/ or cytokine treatments failed due to low response rates and high toxicity.1,2 However, improved knowledge of interactions between tumor cells and the immune system has led to a change in strategy. Recently, it has been shown that tumors activate immune checkpoint pathways which suppress any anti tumor immune responses.3 Immune checkpoint inhibitors block these pathways and can evoke the power of cytotoxic CD8+ T lymphocytes to eliminate cancer cells.
Editorial Boosting Response: The Impact of Immune * *Corresponding author Checkpoint Inhibitors on Radiation Jennifer Sims-Mourtada, PhD Senior Clinical Scientist Center for Translational Cancer Treatment Schedules Research Helen F Graham Cancer Center and 1,2,3,4 2,5* Firas Mourtada and Jennifer Sims-Mourtada Research Institute Christiana Care Health Services Inc.
Newark DE 19713, USA; 1 Department of Radiation Oncology, Christiana Care Health Services Inc., Newark DE 19713, Departments of Biological Sciences USA and Medical Laboratory Sciences 2 Center for Translational Cancer Research, Helen F Graham Cancer Center and Research University of Delaware Newark DE 19713, USA Institute, Christiana Care Health Services Inc., Newark DE 19713, USA Tel. 302-623-4648 3Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University, Fax: 1-302- 623 -4314 Philadelphia, PA 19107, USA E-mail: jsimsmourtada@christianacare.org 4 Department of Radiation Physics, MD Anderson Cancer Center, Houston, TX 77030, USA 5Departments of Biological Sciences and Medical Laboratory Sciences, University of Dela- Volume 2 : Issue 2 ware, Newark DE 19713, USA Article Ref. #: 1000CSMMOJ2e002 The recent FDA approvals of immunomodulatory drugs such as Nivoluvamab (Op- Article History divo), Pembrolizumab (Keytruda) and Ipilimumab (Yervoy) for treatment of Non-small cell th Received: September 14th, 2015 lung cancer (NSCLC) and melanoma have renewed interest in cancer immunotherapy. Initial th Accepted: September 14th, 2015 attempts to activate the immune system to improve anti-tumor immunity by vaccination and/ th 1,2 Published: September 15 , 2015 or cytokine treatments failed due to low response rates and high toxicity. However, improved knowledge of interactions between tumor cells and the immune system has led to a change in Citation strategy. Recently, it has been shown that tumors activate immune checkpoint pathways which Mourtada F, Sims-Mourtada J. Boost- suppress any anti-tumor immune responses.3 Immune checkpoint inhibitors block these path- ing response: the impact of immune + ways and can evoke the power of cytotoxic CD8 T lymphocytes to eliminate cancer cells. checkpoint inhibitors on radiation treatment schedules. Cancer Stud The first immune checkpoint inhibitor Ipilimumab, a monoclonal antibody to CTLA-4, Mol Med Open J. 2015; 2(2): e8-e10.
doi: 10.17140/CSMMOJ-2-e002 was approved by the US FDA in 2011 for the treatment of unresectable or metastatic melanoma and has since shown some efficacy for the treatment of other solid tumors such as lung, head and neck, and sarcomas in combination with standard treatment regimens. CTLA-4 is a surface receptor which inhibits T-cell co-stimulatory signals and prevents cytotoxic T-cell activation. + By blocking CTLA-4 signaling, ipilimumab allows activation of anti-tumor CD8+ T-cell re- sponses. The success of ipilimumab led the way for development of other immune checkpoint inhibitors such as Nivoluvamab and Pembrolizumab which both target the PD-1 (programmed death-1) pathway. PD-1 ligands (PD-1L) are released by tumor cells and lead to immuno- + suppressive effects including reduced CD8+ T-cell proliferation and decreased production of immunostimulatory cytokines.4 Blocking the PD-1 pathway results in increased activation of effector T cells and increased tumor immunity.
In spite of promising results with these new immunotherapies, many patients do not respond or develop resistance, suggesting the need for combination therapies. Additionally, response to these therapies may be limited to patients who have a pre-existing density of clonal + 5 CD8+ T cells.5 Nonetheless, responses may be improved by optimizing the immunostimulatory effects of standard therapies may to augment immune responses elicited by these agents and Copyright improve clinical outcomes.
©2015 Sims-Mourtada J. This is an open access article distributed un- Radiation has long been known to enhance anti-tumor immunity due to the release der the Creative Commons Attribu- of tumor specific antigens from dying tumor cells which stimulate T-cell mediated immune tion 4.0 International License (CC responses. Additionally, radiation has been shown to upregulate many cell surface receptors BY 4.0), which permits unrestricted use, distribution, and reproduction important for immune activation and regulation. Amplification of immune responses by radia- in any medium, provided the origi- tion has been shown in clinical setting but the radiotherapy dose and fractionation regimen has nal work is properly cited.
not been well defined. Animal models have demonstrated that the abscopal effect of radiation can vary depending on the dose and fractionation scheme, with nia recently started a phase I trial for to combine SBRT followed + 8 lower fraction, higher dose treatments eliciting higher CD8+ T- by 4 cycles of ibilimumab for metastatic melanoma patients.8 cell responses and reducing numbers of regulatory T-cells (Treg).6 While toxicity was limited, only 18% of patients showed a par- tial response. Furthermore, stratification by PD-1L expression in In Cancer Letters, Gandhi, et al. recently reviewed evi- the melanoma lesion resulted in significantly higher overall and dence for optimal dose and fractionation to maximize its effect progression free survival in patients with low PD-1L expression on the immune system response against tumor cells.7 In mod- compared to those with high PD-1L expression. This is likely ern radiotherapy, hypofractionation (large dose per fraction) has due to radiation induced upregulation of PD-1L as was observed demonstrated greater tumor dose response, while sparing sur- in animal models after radiation, further highlighting the impor- rounding normal tissue. This is mainly due to advancement in tance of fully understanding the impact of radiation on immuno- technology that enables delivery of higher doses to tumor targets regulatory pathways. These findings suggest the possibility that within 1-2 mm spatial uncertainty using Stereotactic Body Ra- a threshold radiation dose can be delivered by SBRT and may diation Therapy (SBRT) with real-time imaging and radiation enhance immunogenicity, but also caution that a balance must beam gating. Currently, treatment schedules for SBRT have not be met between radiation induced immune stimulation and im- been standardized to enhance the abscopal effect. More work is munosuppression.
needed to understand the impact of SBRT dose and fractionation schemes on cytotoxic and regulatory T-cells in a clinical setting. New radiation treatment planning tools are needed to model not only the SBRT dose distributions but the impact that it Likewise, the interactions between newly approved might entail if an immunotherapy regimen is also administered.
immunomodulators and radiation are not clearly understood. A The question is how can we determine the hypofractionation study recently published in Nature suggests that dual inhibition schedule in a clinical setting when this is likely to be dependent of immune checkpoints in combination with radiation therapy on immune status and tumor characteristics that may be patient can increase response.8 This study showed a synergistic effect specific? New mathematical and physical treatment models, sto- between radiation and anti-CTLA4 therapy. Treatment of tu- chastic or deterministic, have been proposed for hypofraction- mors with anti-CTLA4 therapy inhibited T-regulatory cells and ated radiotherapy with concurrent chemotherapy. For example, + increased the CD8+ T-cell to Treg ratio, while radiation enhanced Ohri, et al. published a paper titled “Can Drugs Enhance Hy- the diversity of T-cell receptors to improve antigenic targeting.
pofractionated Radiotherapy? A Novel Method for Modeling Radiosensitization Using in vitro Data”.12 In traditional prac- However, while the combination of radiation and anti- tice, the radiotherapy dose regimen starts with calculating the CTLA-4 therapies produced responses in some patients, a sub- absorbed dose to tissue (in units of Gray (Gy), which is then set of patients developed resistance to therapy. This resistance folded with the generalized linear quadratic (gLQ) model to was shown in animal models of melanoma to be due to radia- calculate the biological effective dose or BED or biologically tion induced up regulation of PD-1L, which could overcome the equivalent dose in 2-Gy per fraction (EQD2). This mathematical inhibition of regulator T-cells by CTLA-4. Other studies have model implementation with and without radiosensitizing agents confirmed the radiation induced up regulation of PD-1L in the was demonstrated. Similar simulation models for SBRT and im- tumor microenvironment can be evoked by INFγ produced by munotherapy agents might be beneficial to optimize the dose per T cells following radiation exposure.9 To maximize the immu- fraction prior to initiation of the immunotherapy. Tumor charac- nostimulatory effect of the radiation response, it is necessary to teristics, as well as levels of circulating regulatory, cytotoxic and understand the kinetics of radiation induced immunostimula- memory T cells which can be monitored prior to and over the tion and up regulation of immunomodulatory receptors as this course of treatment, may also help to guide the SBRT treatment may impact further optimization of clinical radiation treatment planner. Currently, such models remain in the research domain, schedules.
but translation to the clinical setting could potentially improve the successes of cancer immunotherapy.
As of this writing, mostly anecdotal clinical data have shown some benefit in combining radiation treatment with im- CONFLICTS OF INTEREST mune checkpoint inhibitors to improve response. Previous clini- cal studies using cytokine therapy to boost anti-tumor immunity The authors have no conflicts of interest with this article.
showed the effects of the immunostimulatory cytokine IL-2 can be augmented with SBRT in metastatic renal cell carcinoma