Glioma

REVIEW
Year
: 2019  |  Volume : 2  |  Issue : 1  |  Page : 3--6

Importance of iatrogenic immunosuppression in the treatment of patients with high-grade glioma with immunotherapy


Anna F Piotrowski1, Stuart A Grossman2,  
1 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
2 Department of Medicine, Oncology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Correspondence Address:
Dr. Anna F Piotrowski
Memorial Sloan Kettering Cancer Center, New York, NY
USA

Abstract

Treatment-related lymphopenia is a poor prognostic factor for overall survival in patients with high-grade glioma and predicts suboptimal response to immune therapies. Immunotherapy is conceptually an appealing approach in adults with high-grade glioma given that effector lymphocytes are capable of penetrating the blood–brain barrier. However, 40% of these patients develop severe lymphopenia (CD4 counts <200) following concurrent radiation and temozolomide. These low lymphocyte counts are associated with inferior survival. Research suggests that this iatrogenic immunosuppression is attributed to the inadvertent radiation of circulating lymphocytes as they traverse the irradiated field. Lymphocyte subtypes are universally affected by this radiation toxicity. These findings have been reproduced in animal studies, and clinical correlations have been demonstrated in patients with various malignancies. This lymphopenia has been linked with failure to respond to immunologic interventions. Recent insights into the etiology of this radiation-induced lymphopenia have triggered a variety of novel approaches to prevent or restore immunologic function in this patient population. These include altering radiation plans, reducing the number of lymphocytes passing through the radiation field, harvesting lymphocytes before and reinfusing them after radiation, and using growth factors to restore lymphocyte counts. This manuscript reviews critical relationships between treatment-related lymphopenia and immunotherapy outcomes in patients with high-grade gliomas and novel approaches to these issues.



How to cite this article:
Piotrowski AF, Grossman SA. Importance of iatrogenic immunosuppression in the treatment of patients with high-grade glioma with immunotherapy.Glioma 2019;2:3-6


How to cite this URL:
Piotrowski AF, Grossman SA. Importance of iatrogenic immunosuppression in the treatment of patients with high-grade glioma with immunotherapy. Glioma [serial online] 2019 [cited 2019 Sep 18 ];2:3-6
Available from: http://www.jglioma.com/text.asp?2019/2/1/3/255156


Full Text

 Introduction



Improvements in the outcome of patients with high-grade glioma have been extremely limited over the past several decades.[1] Despite dramatic advances in imaging and surgical care, this cancer remains incurable even if it is detected early and is surgically accessible. Similarly, extensive research focused on improving the efficacy of radiation therapy has evaluated escalating radiation doses, employing different field sizes and dose fractions, using radiation sensitizers, and implanting radiation seeds within the tumor without much progress. Despite decades of trials with chemotherapeutic and biologic agents, only temozolomide has been demonstrated to improve overall survival.[2] Unfortunately, its impact on patient outcomes has been limited. In patients with glioblastoma who have a good performance status and are eligible for clinical trials, temozolomide provides an increase in overall survival of <3 months and in the 60% of patients who are O6-methylguanine-DNA methyltransferase unmethylated; it appears to provide little to no clinical benefit.[3] Increasing the dose or duration of temozolomide has not improved outcomes, and the cure rate with aggressive multimodality therapy remains close to zero.[4] Efforts to implant chemotherapy-laden biodegradable polymers into glioblastomas at the time of resection[5] or using low intensity, alternating electric fields to disrupt cell division after completing radiation therapy,[6] have had only minimal impact on survival. The results of extensive trials of targeted and antiangiogenesis agents have been very disappointing.[7],[8] As 98% of drugs approved by the U. S. Food and Drug Administration do not enter the brain in therapeutic concentrations, the efficiency of the blood–brain barrier remains a major factor limiting the efficacy of systemically administered chemotherapeutics in this difficult to treat cancer.[9]

Given the significant barriers to progress with surgery, radiation, and chemotherapy, alternative treatment approaches are needed to improve outcomes for patients with high-grade glioma. Immunotherapy aims to stimulate the systemic immune response, and lymphocytes can penetrate the blood–brain barrier, unlike most pharmaceutical agents. However, as has been documented in early clinical trials, success with immunotherapy interventions will likely not come easily. The lack of success to date may be attributed to the low mutational burden[10] and the immunologically “cold” profile of high-grade glioma,[11] the necessary use of glucocorticoids to reduce brain edema, and the lymphotoxicity that accompanies radiation, temozolomide, and steroids. This manuscript reviews critical relationships between treatment-related lymphopenia and immunotherapy outcomes in patients with high-grade gliomas and novel approaches to these issues.

 Mechanism of Treatment-Related Lymphopenia



The incidence, severity, and duration of Grade III-IV lymphopenia and the association between lymphopenia and survival were first described in patients with newly diagnosed high-grade glioma following radiation and temozolomide in 2011. The National Institutes of Health-funded New Approaches to Brain Tumor Therapy found that of 96 patients with high-grade glioma, 40% became severely lymphopenic (defined as CD4 count <200 cells/mm3) and remained severely depressed for at least 1 year of follow-up. Multivariate analysis showed that lymphopenia at 2 months is an independent prognostic factor for shorter survival due to tumor progression.[12] Subsequent studies by the same investigators documented that similar lymphopenia toxicity profiles followed radiation in elderly glioblastoma patients,[13] patients with head and neck,[14],[15] lung,[16] pancreatic,[17],[18] cervical,[19] esophageal,[20],[21] rectal,[22] and pediatric malignancies.[23] Interestingly, nonsmall-cell lung cancer patients who receive upfront radiation immediately become lymphopenic, whereas those who received neoadjuvant chemotherapy only become lymphopenic when the radiation is added.[24] Moreover, the association between low lymphocyte counts and overall survival is not limited to patients with high-grade glioma.[25] In retrospect, there were many reports in the 1960s and 1970s documenting that radiation to almost any site resulted in severe and sustained lymphopenia,[26],[27] but its prognosis for poor survival was not firmly established until 2011 when the high-grade glioma study was published.

Radiation of extracorporeal circulating blood has been shown to result in profound lymphopenia in multiple animal studies as well as a series of transplant patients. Dr. Cronkite et al.'s group[28] at the Brookhaven National Laboratory established that severe and long-lasting lymphopenia in calves can be produced by radiating an externalized catheter connecting an artery and a vein or the thoracic duct and a vein. Oldendorf et al.[29] described a surgical technique for delivering ionizing radiation to a large artery graft within a metal shield in living dogs. In 1965, Wolf and Hume[30] used a radioactive intra-arterial implant to produce lymphopenia in dogs. Storb et al.[31] carried out continuous extracorporeal irradiation of blood and noted lymphoid hypoplasia in addition to lymphocytopenia in baboons. These investigators reviewed hematoxylin and eosin-stained sections of lymph nodes and noted decreased cellularity and atrophic germinal centers immediately after radiation and normalization after 5–8 weeks. In the early 1970s, when potent immunosuppressive drugs were unavailable, patients awaiting kidney transplant had their peripheral blood circulating in dialysis machines irradiated to effectively induce sustained immunosuppression.[32]

A newly developed animal model of radiation-induced lymphopenia following cranial irradiation has recently been published. Using a small animal radiation research platform, C57 BL/6 and BALB/c mice were given focal brain irradiation at multiple doses and fractionation schemes: 1, 2, 3 Gy × 5 fractions, 2 Gy × 30 fractions, and 4 Gy × 10 fractions. In this study, there was no significant radiation exposure to extracranial sites such as lymphoid organs or bone marrow. Similar to humans, the mice became lymphopenic after the radiation and lost 70% of their circulating lymphocytes. Unlike humans, lymphocyte counts in these mice recovered 3 weeks following the completion of radiation. Postmortem examinations of inguinal lymph nodes, far outside of the radiation field, demonstrated remarkable histopathologic changes demonstrating systemic lymphodepletion.[33]

Recent studies strongly suggest that this iatrogenic immunosuppression occurs largely due to the inadvertent radiation of circulating lymphocytes as they pass through the radiation beam. Lymphocytes are the most radiosensitive cells in the body. A mathematical model has been published which estimates the radiation dose that lymphocytes receive while passing through the radiation field. A typical high-grade glioma treatment plan (8 cm tumor, 60 Gy in 30 fractions) was constructed using the Pinnacle radiation planning system (Philips Healthcare, Baltimore, MD, USA). Radiation doses to circulating cells were analyzed using MatLab (MathWorks, Natick, MA, USA). The model determined that radiation from the first fraction of radiation will kill 6% of all circulating lymphocytes and that with the typical 30 fractions over 98% of circulating lymphocytes had received the lymphotoxic dose.[34] A prospective immunophenotypic analysis of 20 patients with glioblastoma treated with standard radiation and temozolomide demonstrated that all subsets of B-cells, T-cells, and natural killer cells are severely decreased by standard radiation treatment.[35] The clinical, animal, and modeling studies described above strongly suggest that circulating blood should now be considered an “organ at risk” for radiation toxicities based on its effect on the immune system.[36],[37]

The immune system has long been thought to play a key role in cancer surveillance and therapy. This concept was pioneered by Dr. Coley[38] in 1890 when he injected bacteria directly into inoperable tumors in an attempt to stimulate an immune response against the cancer. This belief continues to underpin the current enthusiasm regarding the use of novel immunotherapy, such as checkpoint inhibitors.[11] If one believes that enhancing the capacity of the immune system to recognize and eradicate cancer will improve survival, then it is equally apparent that accidental injury to the immune system might compromise clinical outcomes. As outlined above, radiation to circulating lymphocytes results in a severe, persistent, and unintended injury to the immune system. The severe lymphopenia occurs in about 40% of treated patients and is associated with reduced survival which is likely due to the patient's impaired immune system to control growth of the cancer. As lymphocytes are the effector cells required for a response to immunotherapy, treatment-related lymphopenia clearly has a significant detriment on response to checkpoint inhibitor therapy. This is highlighted by a recent study of 167 patients with solid tumors who received either nivolumab or pembrolizumab. Those with persistent lymphopenia, usually after radiation therapy, had fewer responses, fewer immune side effects, and a shorter time to progression than those with higher lymphocyte counts.[39]

 Strategies to Restore Immune Function



Immunotherapy trials in patients with high-grade glioma face a number of significant challenges including their low mutational burden, immunologically “cold” profile of high-grade glioma, and the frequent use of glucocorticoids to control peritumoral vasogenic edema.[11] While these tumor-associated factors are unmodifiable, recent insights into the etiology of radiation-induced lymphopenia have generated optimism that this can be effectively prevented or repaired using a variety of strategies. These are briefly outlined below.

Novel radiation approaches

The mathematical model described above has identified important and actionable variables that contribute to the immunosuppression. The radiation dose delivered to circulating blood with a brain treatment plan is likely to be primarily dependent on volume of the radiation field, number of radiation fractions, and dose rate.[36] Studies in other systemic cancers have clearly shown that reducing the size of the treatment field (i.e., using stereotactic radiation) and reducing the number of administered fractions have a significant effect on posttreatment lymphocyte counts.[40],[41] An interesting experimental approach uses flash radiation, which provides radiation in milliseconds rather than minutes, and is likely to dramatically reduce radiation exposure to circulating lymphocytes.[42]

Novel prevention approaches

Two recently completed feasibility trials in patients with high-grade glioma have explored innovative ways to spare lymphocytes from radiation. The first used a sphingosine-1-phosphate inhibitor which homes lymphocytes in lymphoid organs resulting in approximately a 70% reduction in the total number of circulating lymphocytes. This study was designed to determine if the combination of this sphingosine-1-phosphate inhibitor and radiation with temozolomide resulted in opportunistic infections that would limit its utility. No severe opportunistic infections were observed clearing the way for further prospective studies (NCT02490930). A second study evaluated the feasibility of harvesting lymphocytes before radiation and reinfusing them on completion of radiation. This was also found to be safe; however, the number of lymphocytes harvested from one peripheral line was less than ideal.[43]

Novel restoration approaches

Interleukin-7 is a major regulator of lymphocytes and specifically CD4 counts. Compensatory high levels of this cytokine should be noted when CD4 counts are low and undetectable levels are seen when there are adequate numbers of these lymphocytes. This has been well documented in patients with acquired immune deficiency syndrome, sepsis, and in chemotherapy-induced lymphopenia. However, patients with high-grade glioma and severe lymphopenia from radiation have been found to have very low interleukin-7 levels for reasons that are not understood.[44] This information has led to a currently active clinical trial within the NIH-funded Adult Brain Tumor Consortium which is conducting the first study of interleukin-7 in severely lymphopenic patients when they complete 6 weeks of radiation with temozolomide (NCT03687957).

 Conclusion



Iatrogenic immunosuppression secondary to radiation therapy adds another challenge to the treatment of patients with high-grade glioma with immunotherapy. However, unlike those unmodifiable factors such as low mutational burden, a “cold” tumor, and the need to use glucocorticoids to treat peritumoral brain edema, there are encouraging efforts underway to prevent or repair inadvertent damage to the immune system from radiation. Priority should be given to this line of research to optimize the efficacy of immunotherapy in this aggressive cancer.

Financial support and sponsorship

This work was funded in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.

Conflicts of interest

There are no conflicts of interest.

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