Chelsea C. Pinnix, MD, PhD
The emergence of immune checkpoint inhibitors as an effective treatment strategy is a result of increased understanding of the elaborate relationship between tumor cells, their microenvironment and the host immune response. Laboratory and clinical data suggest that radiation therapy elicits immune-mediated anti-neoplastic effects locally as well as systemically. The coupling of external beam radiation therapy with immune checkpoint inhibition provides an opportunity for synergistic anti-tumor effects. This approach has been explored initially among patients with solid tumors, however, as investigations into immune checkpoint inhibition have skyrocketed among all malignancies, the potential combinatory role of radiation therapy with immune checkpoint inhibition among patients with hematologic malignancies remains undefined. We explore the rationale, existing data, and future perspectives of combined modality therapy with immune checkpoint blockade and external beam radiation therapy among patients with lymphoma.
Immune homeostasis is necessary to mount appropriate destructive immune responses towards threatening pathogens while limiting excessive responses towards host tissues that would result in autoimmunity. This is achieved via a highly regulated balance between T-cell co-stimulatory and inhibitory signals, which collectively are known as immune checkpoints. Immune checkpoints are essential for the maintenance of peripheral tolerance as well as the prevention of host tissue damage under circumstances of infection and inflammation. Immune suppressive checkpoint proteins have been identified that negatively regulate the immune system, resulting in suppressed T-cell inflammatory responses and prevention of autoimmunity (CTLA-4, PD-1, LAG-3, TIM-3, KIRs). Tumor cells can exploit these pathways and ultimately elude immunosurveillance by activating these checkpoint receptors via ligand over-expression resulting in T-cell exhaustion. Immune activating proteins have also been identified (4-1BB, GITR) and represent an additional viable therapeutic target. Through activation of co-stimulatory receptors, or antagonization of inhibitory signals, T-cell responses toward tumor antigens can be enhanced and represent an exciting cancer therapeutic strategy that is transforming the oncology world.
Several investigations demonstrate the capacity for local radiation therapy to engender systemic (abscopal) anti-tumor effects that are immune-mediated. Radiation induced effects on tumor cells are complex and multifocal and have recently been reviewed in detail by Weichselbaum et al1. The local and distant immune responses elicited by radiation therapy can have disparate effects on tumor activity: resulting either in continued tumor growth or tumor cell death. The concept of improving anti-neoplastic activity of immune checkpoint inhibitors by conjoining them with radiation therapy has been explored in animal models and is the focus of ongoing clinical trials, mainly in the setting of solid malignancies. This strategy is also valid among patients with hematologic malignancies where innovative combination therapies to improve responses to immune checkpoint blockade are needed to expand the potential therapeutic benefit of immunotherapy.
Hodgkin lymphoma is characterized by a small number of characteristic neoplastic Reed- Sternberg cells coupled with a dense ineffective inflammatory tumor microenvironment. In Hodgkin lymphoma, alterations of chromosome 9p24 that increase the expression of programed death receptor ligands 1 and 2 (PD-L1 and PD-L2) have been frequently identified and suggest that patients with HL may be uniquely positioned to derive benefit from program cell death receptor 1 (PD-1) blockade with immune checkpoint inhibitors.2,3 Green et al performed an integrative analysis of Hodgkin lymphoma cell lines and primary Hodgkin lymphoma tumor specimens,3 combining DNA copy number based on high-density single nucleotide polymorphism array and gene transcript data. Through this combined integrative analysis, PD-L1 and PD-L2 were identified as key targets of the 9p24.1 amplification. Furthermore, PD-L1 gene amplification was associated with enhanced PD-1 ligand expression among primary Hodgkin lymphoma tumors. In a study of 108 biopsy specimens from newly diagnosed patients with Hodgkin lymphoma, 97% of tumors had alterations of the PD-L1 and PD-L2 loci, either by copy gain (56%), amplification (36%) or polysomy (5%).2 Furthermore, 9p24.1 amplification was associated with shorter progression-free survival (PFS) as well as advanced stage disease. These findings taken together suggest a genetic basis for PD-1 pathway activity in classical Hodgkin lymphoma.
As a consequence of 2 single arm, multicenter trials, the FDA in May 2016 granted approval of nivolumab for the treatment of Hodgkin lymphoma that relapsed or progressed after autologous stem cell transplantation (ASCT) and post-transplant brentuximab vedotin (an antibody–drug conjugate that targets CD30). A phase I study of 23 patients treated with single agent nivolumab (Checkmate 039, NCT01592370) for relapsed and refractory Hodgkin lymphoma reported an overall response rate (ORR) of 87% and a complete response rate of 17%. The rate of PFS at 24 weeks was 86%.4 In the phase II study of 80 patients with relapsed and refractory classical Hodgkin lymphoma that progressed after ASCT and treatment with brentuximab, the ORR was 66% and the complete response rate was 9%.5 In March of 2017, pembrolizumab was approved for the treatment of relapsed and refractory Hodgkin lymphoma among pediatric and adult patients that have failed 3 or more lines of therapy based on a non-randomized multicenter trial of adult patients [KEYNOTE-087, ClinicalTrials.gov identifier NCT02453594].6 A total of 210 patients were treated on 3 cohorts that were defined based on progression of Hodgkin lymphoma (cohort 1: progression after ASCT and brentuximab vedotin; 2: progression after salvage chemotherapy and brentuximab and therefore ineligible for ASCT or 3: ASCT without posttransplant brentuximab). Among all patients the ORR was 69% (95% CI, 62.3% to 75.2%) with a complete response rate of 22.4% (95% CI, 16.9% to 28.6%). The median duration of response was not reached among all 3 cohorts with median follow-up of 10.1 months. Three quarters of patients had a response that lasted at least 6 months (75.2%). Treatment was generally well tolerated with the most frequent consequential adverse events being hypothyroidism (12.4%) and pyrexia (10/5%). Grade 3 and 4 therapy-related adverse events were rare and included neutropenia (2.4%), diarrhea (1%) and dyspnea (1%). Pneumonitis occurred in 2.9% of patients and was grade 1 or 2. No grade 3 or 4 pneumonitis occurred.
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