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A Patient with HIV Treated with Ipilimumab and Stereotactic Radiosurgery for Melanoma Metastases to the Brain

A Patient with HIV Treated with Ipilimumab and Stereotactic Radiosurgery for Melanoma Metastases... Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2013, Article ID 946392, 4 pages http://dx.doi.org/10.1155/2013/946392 Case Report A Patient with HIV Treated with Ipilimumab and Stereotactic Radiosurgery for Melanoma Metastases to the Brain 1 2 3 3 Jacob Ruzevick, Sarah Nicholas, Kristin Redmond, Lawrence Kleinberg, 4 1,4 Evan J. Lipson, and Michael Lim Departments of Neurosurgery, eTh Johns Hopkins University School of Medicine, Phipps 123 600 N. Wolfe Street, Baltimore, MD 21287, USA University of Maryland School of Medicine, Baltimore, MD 21210, USA Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Oncology, eTh Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence should be addressed to Michael Lim; mlim3@jhmi.edu Received 17 September 2013; Accepted 31 October 2013 Academic Editors: K. Jamil and P. F. Lenehan Copyright © 2013 Jacob Ruzevick et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cancers, such as melanoma, that are associated with immune deficiencies are a major cause of morbidity and mortality in HIV- infected patients. Once patients develop melanoma metastases to the brain, treatment is oeft n limited to palliative surgery and/or radiation. Ipilimumab, a CTLA-4 antagonist, has been shown to improve the median survival of patients with metastatic melanoma. However, available data regarding the safety and efficacy of ipilimumab in HIV-infected patients who develop intracranial melanoma metastases is limited. Here we report our experience administering ipilimumab to a patient with HIV-AIDS who developed multiple intracranial melanoma metastases. Following treatment, our patient showed improvement in systemic tumor control without any apparent interference with antiretroviral treatment. 1. Introduction monotherapy for patients with intracranial melanoma metas- tasesresulting in amediansurvivalof7and14monthsinpro- Melanoma is perhaps the most immunogenic human cancer spective phase II and retrospective studies, respectively [4, 5]. and, as a result, is more prevalent in HIV-infected indi- Ipilimumab antagonizes the CTLA-4 protein on the surface vidualsthaninthe generalpopulation[1]. Furthermore, of T cells, which acts as coinhibitory signal (i.e., immune HIV-positive patients diagnosed with melanoma experience checkpoint) aeft r ligand binding. By preventing signaling shorterdisease-freesurvivaland overallsurvivalthantheir through the CTLA-4 protein, immune cell tolerance and immunocompetent counterparts [2]. Currently there is a exhaustion are decreased, leading to a more active antitumor paucity of data regarding the treatment of patients with response by the host immune system. HIV who develop intracranial metastases. While surgery and CTLA-4 may also play a role in the progression of HIV. whole brain radiation therapy or stereotactic radiosurgery In onestudy,levelsofCTLA-4expressiononCD4+Tcellsof (SRS) can palliate symptoms of neurologic decline, treatment HIV-infected patients were inversely correlated with absolute is almost invariably followed by progression of local and/or CD4+ T cell count and directly correlated with viral load systemic disease. [6]. Furthermore, CTLA-4 signaling resulted in increased expression of CCR5 and a greater susceptibility of CD4+ cells In 2011, the U.S. Food and Drug Administration approved ipilimumab (Yervoy, Bristol-Myers Squibb, Princeton, NJ, to infection [7]. The combination of SRS and ipilimumab has recently USA), a CTLA-4 antagonist, for the treatment of metastatic been studied in a retrospective cohort of patients with mela- melanoma aer ft it was shown to improve median over- allsurvival[3]. Recently, ipilimumab has been tested as noma brain metastases and showed improved survival as 2 Case Reports in Oncological Medicine isodose line. A restaging FDG-PET/CT scan demonstrated multiple metastases in the right and left hepatic lobes, left iliac external lymph nodes, left deep inguinal nodes, left distal thigh, left popliteal fossa, left anterior tibialis muscle, and right femur. Eleven days following SRS, he presented to the Emer- gency Department with weakness in his left upper extremity. An MRIrevealedanintervalincreaseinall brainlesions. eTh rightoccipitallobelesionmeasured2.4cm whilethe left frontal lobe lesion measured 1 cm in greatest diameter. High dose steroids were prescribed as the interval increase in all brain lesions was likely a result of post-SRS inflammation and not true progression of underlying disease. Interval MRI scans over the next 6 months showed stabilization of brain metastases while interval FDG-PET/CT imaging showed stabilization or complete resolution of extracranial lesions. Seven months aer ft completion of SRS, a single new brain metastasis was seen in the left supramarginal Figure 1: T1-postcontrast MRI showing a 2.7 × 3.5 × 3.1 cm gyrusand wastreated usingSRS 2000cGytothe 73%isodose hemorrhagic mass involving the right precentral gyrus. Following line in a single fraction. Representative pretreatment and 8- surgical resection, pathology confirmed metastatic melanoma. month posttreatment MR imaging are shown in Figure 2. At the time of paper preparation the patient is nine months post-surgery after resection of his rfi st brain metas- compared to SRS alone [8]. However, little has been reported tasis. He has remained on efavirenz/emtricitabine/tenofovir, about this treatment combination in patients with HIV. Here, though his adherence to the HAART therapy has been poor. we report our experience treating a patient with HIV and 3 His absolute CD4 counts have ranged from 126 to 449/mm multiple brain metastases with ipilimumab and concomitant with an undetectable viral load. He is able to function at his SRS. baseline. He experienced only minor gastrointestinal discom- fort throughout his treatment with ipilimumab and SRS. His extracranial metastases have remained stable or resolved. 2. Case Report A 48-year-old Caucasian male was diagnosed with HIV- 3. Discussion AIDS in 2009 aer ft presenting with oral candidiasis. His absolute CD4 count was 38/mm with a viral load of In our patient, the administration of SRS and ipilimumab was 176,000 copies/mL. He began highly active antiretroviral well tolerated and caused signica fi nt regression of widespread therapy (HAART) with efavirenz/emtricitabine/tenofovir melanoma metastases. Although the benefit of combinatorial (Atripla, Bristol-Myers Squibb). Also present at the time of therapy in this particular patient is unclear, synergy has been presentation was a melanoma on the right cheek, which was observed in animal models and human trials, suggesting subsequently excised. Due to neuropathy, the patient was that treatment approaches involving multiple mechanisms unable to tolerate lymphoscintigraphy, preventing sentinel of action may be more likely to overcome an immunosup- node localization. pressive tumor microenvironment than monotherapy [9]. Two years later, he experienced progressive, left-sided Knisely and colleagues reported in one retrospective study facial, upper extremity, and lower extremity numbness and that patients who received ipilimumab in combination with weakness. MRI of the head and spine revealed a hemorrhagic radiotherapy had a median survival of 21.3 months as com- mass involving the right precentral gyrus measuring 2.7× 3.5 pared to 4.9 months for patients who received radiotherapy × 3.1 cm with surrounding vasogenic edema (Figure 1). He alone [8]. In a prospective, randomized controlled trial, was admitted to Johns Hopkins Hospital and underwent a ipilimumab combined with dacarbazine improved overall craniotomy for tumor resection. Pathologic evaluation con- survival compared to dacarbazine alone in patients with firmed metastatic melanoma. metastatic melanoma [10]. Three weeks aeft r surgery, he began treatment with Reports describing HIV-positive patients with metastatic ipilimumab, administered at the standard dose of 3 mg/kg melanoma treated with immunotherapy are limited. of body weight every three weeks for four doses. One week Interleukin-2 was tested as an adjuvant to HAART therapy in following the first dose of ipilimumab, he received an SRS an attempt to stimulate antitumor activity but did not show a boost to the tumor bed of 2100 centigray (cGy) in 3 fractions survival benefit in a single patient [ 11]. Burke and colleagues prescribed to the73% isodoselineusing Cyberknife.Atthe reported on a single patient with HIV and stage IV melanoma time of the planning MRI, two more brain metastases were who was treated with ipilimumab and experienced disease noted: one in the right occipital lobe and another in the left regression without dose-limiting toxicities [12]. frontal lobe, each measuring 7 mm in greatest diameter. Both Preclinical studies describing the role of immune check- were treated with SRS 2000 cGy in a single fraction to the 73% point molecules, such as CTLA-4, in HIV pathogenesis Case Reports in Oncological Medicine 3 Radiation + ipilimumab Post Pre Right precentral gyrus mass (postsurgical resection) Radiation + Ipilimumab Left frontal middle gyrus mass Right medial occipital lobe mass Figure 2: T1-postcontrast MRI showing pretreatment (left column) and 8-month posttreatment (right column) MR imaging of melanoma brain metastases treated with SRS and ipilimumab. have also been revealing. One group has reported increased multiple systemic metastases. Although the contribution of viral replication following blockade of CTLA-4 in primates each therapeutic modality is unknown, a synergy reminiscent [13]. Studies of HIV-specific T cells demonstrate expression of the abscopal eeff ct is possible. eTh abscopal eeff ct describes of programmed death-1 (PD-1), another checkpoint mole- a phenomenon wherein a single lesion is irradiated, causing cule, which is associated with T cell exhaustion and progres- regression of distant metastases. While the exact mechanism sion of HIV [14]. Blocking the immunoregulatory pathway remains to be elucidated, the improvement in systemic met- comprisedofeitherCTLA-4orPD-1anditsligandsmayrein- astases is likely immune mediated. Lugade et al. reported vigorate a host immune response against a chronic infection that melanoma-bearing mice that had been irradiated had such as HIV. improved antigen presentation and an increase in interferon- Follow-up FDG-PET/CT imaging of our patient aer ft gamma secreting CD8+ cells aeft r peptide stimulation [ 15]. ipilimumab and SRS showed stabilization or regression of Similarly, in a single patient case report, Stamell et al. 4 Case Reports in Oncological Medicine reported the resolution of systemic melanoma metastases patient with HIV with metastatic melanoma,” Journal of Clinical Oncology,vol.29, no.32, pp.e792–e794,2011. and a greater-than-7-year survival in a patient treated with intracranial radiation in combination with ipilimumab [16]. [13] V.Cecchinato, E. Tryniszewska,Z.M.Maetal.,“Immune acti- vation driven by CTLA-4 blockade augments viral replication Based on our patient’s experience and the few cases at mucosal sites in simian immunodeficiency virus infection,” reported in the medical literature, further evaluation of the Journal of Immunology, vol. 180, no. 8, pp. 5439–5447, 2008. benefit of radiotherapy and immunotherapies such as ipili- [14] C. L. Day, D. E. Kaufmann, P. Kiepiela et al., “PD-1 expression mumab to patients with metastatic melanoma and underlying on HIV-specific T cells is associated with T-cell exhaustion and HIV infection is warranted. Outcomes of interest include disease progression,” Nature,vol.443,no. 7109,pp. 350–354, tumor response to therapy, eeff ct on CD4 count and viral load, and changes in function of HIV-specific T cell function. [15] A. A. Lugade, J. P. Moran, S. A. Gerber, R. C. Rose, J. G. Frelinger, and E. M. Lord, “Local radiation therapy of B16 mel- References anoma tumors increases the generation of tumor antigen-speci- fic effector cells that traffic to the tumor,” Journal of Immunology, [1] M. J. Silverberg, C. Chao, W. A. Leyden et al., “HIV infection, vol. 174, no.12, pp.7516–7523,2005. immunodeficiency, viral replication, and the risk of cancer,” [16] E. F. Stamell, J. D. Wolchok, S. Gnjatic, N. Y. Lee, and I. Brownell, Cancer Epidemiology Biomarkers and Prevention,vol.20, no.12, “eTh Abscopal eeff ct associated with a systemic anti-melanoma pp. 2551–2559, 2011. immune response,” International Journal of Radiation Oncology, [2] L.K.Rodrigues,B.J.Klencke,K.Vin-Christianetal., Biology, Physics, vol. 85, no. 2, pp. 293–295, 2013. “Altered clinical course of malignant melanoma in HIV-positive patients,” Archives of Dermatology,vol.138,no. 6, pp.765–770, [3] F.S.Hodi, S. J. O’Day, D. F. McDermottetal.,“Improved sur- vivalwithipilimumabinpatientswithmetastaticmelanoma,” New England Journal of Medicine,vol.363,no. 8, pp.711–723, [4] K. Margolin, M. S. Ernstoff, O. Hamid et al., “Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial,” The Lancet Oncology ,vol.13, no.5,pp. 459–465, [5] J. S. Weber, A. Amin, D. Minor, J. Siegel, D. Berman, and S. J. O’Day, “Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial,” Melanoma Research,vol.21, no.6,pp. 530– 534, 2011. [6] Q.Leng, Z. Bentwich,E.Magen,A.Kalinkovich,and G. Borkow, “CTLA-4 upregulation during HIV infection: associ- ation with anergy and possible target for therapeutic interven- tion,” AIDS,vol.16, no.4,pp. 519–529, 2002. [7] J.L.Riley,K.Schlienger, P. J. Blairetal.,“Modulation of sus- ceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule,” Journal of Experimental Medicine,vol.191,no. 11, pp.1987–1997,2000. [8] J.P.Knisely,J.B.Yu, J. Flanigan,M.Sznol,H.M.Kluger, andV. L. Chiang, “Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival,” Journal of Neurosurgery,vol.117,no. 2, pp.227–233,2012. [9] J.L.Frazier,J.E.Han,M.Lim, andA.Olivi,“Immunotherapy combined with chemotherapy in the treatment of tumors,” Neurosurgery Clinics of North America,vol.21, no.1,pp. 187–194, [10] C. Robert,L.Thomas,I.Bondarenkoetal.,“Ipilimumab plus dacarbazine for previously untreated metastatic melanoma,” New England Journal of Medicine,vol.364,no. 26,pp. 2517– 2526, 2011. [11] C. Hoffmann, H. A. Horst, M. Weichenthal, and A. Hauschild, “Malignant melanoma and HIV infection—aggressive course despite immune reconstitution,” Onkologie,vol.28,no.1,pp.35– 37, 2005. [12] M. M. Burke, H. M. Kluger, M. Golden, K. N. Heller, A. Hoos, and M. 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A Patient with HIV Treated with Ipilimumab and Stereotactic Radiosurgery for Melanoma Metastases to the Brain

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Copyright © 2013 Jacob Ruzevick et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Publishing Corporation Case Reports in Oncological Medicine Volume 2013, Article ID 946392, 4 pages http://dx.doi.org/10.1155/2013/946392 Case Report A Patient with HIV Treated with Ipilimumab and Stereotactic Radiosurgery for Melanoma Metastases to the Brain 1 2 3 3 Jacob Ruzevick, Sarah Nicholas, Kristin Redmond, Lawrence Kleinberg, 4 1,4 Evan J. Lipson, and Michael Lim Departments of Neurosurgery, eTh Johns Hopkins University School of Medicine, Phipps 123 600 N. Wolfe Street, Baltimore, MD 21287, USA University of Maryland School of Medicine, Baltimore, MD 21210, USA Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Oncology, eTh Johns Hopkins University School of Medicine, Baltimore, MD, USA Correspondence should be addressed to Michael Lim; mlim3@jhmi.edu Received 17 September 2013; Accepted 31 October 2013 Academic Editors: K. Jamil and P. F. Lenehan Copyright © 2013 Jacob Ruzevick et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cancers, such as melanoma, that are associated with immune deficiencies are a major cause of morbidity and mortality in HIV- infected patients. Once patients develop melanoma metastases to the brain, treatment is oeft n limited to palliative surgery and/or radiation. Ipilimumab, a CTLA-4 antagonist, has been shown to improve the median survival of patients with metastatic melanoma. However, available data regarding the safety and efficacy of ipilimumab in HIV-infected patients who develop intracranial melanoma metastases is limited. Here we report our experience administering ipilimumab to a patient with HIV-AIDS who developed multiple intracranial melanoma metastases. Following treatment, our patient showed improvement in systemic tumor control without any apparent interference with antiretroviral treatment. 1. Introduction monotherapy for patients with intracranial melanoma metas- tasesresulting in amediansurvivalof7and14monthsinpro- Melanoma is perhaps the most immunogenic human cancer spective phase II and retrospective studies, respectively [4, 5]. and, as a result, is more prevalent in HIV-infected indi- Ipilimumab antagonizes the CTLA-4 protein on the surface vidualsthaninthe generalpopulation[1]. Furthermore, of T cells, which acts as coinhibitory signal (i.e., immune HIV-positive patients diagnosed with melanoma experience checkpoint) aeft r ligand binding. By preventing signaling shorterdisease-freesurvivaland overallsurvivalthantheir through the CTLA-4 protein, immune cell tolerance and immunocompetent counterparts [2]. Currently there is a exhaustion are decreased, leading to a more active antitumor paucity of data regarding the treatment of patients with response by the host immune system. HIV who develop intracranial metastases. While surgery and CTLA-4 may also play a role in the progression of HIV. whole brain radiation therapy or stereotactic radiosurgery In onestudy,levelsofCTLA-4expressiononCD4+Tcellsof (SRS) can palliate symptoms of neurologic decline, treatment HIV-infected patients were inversely correlated with absolute is almost invariably followed by progression of local and/or CD4+ T cell count and directly correlated with viral load systemic disease. [6]. Furthermore, CTLA-4 signaling resulted in increased expression of CCR5 and a greater susceptibility of CD4+ cells In 2011, the U.S. Food and Drug Administration approved ipilimumab (Yervoy, Bristol-Myers Squibb, Princeton, NJ, to infection [7]. The combination of SRS and ipilimumab has recently USA), a CTLA-4 antagonist, for the treatment of metastatic been studied in a retrospective cohort of patients with mela- melanoma aer ft it was shown to improve median over- allsurvival[3]. Recently, ipilimumab has been tested as noma brain metastases and showed improved survival as 2 Case Reports in Oncological Medicine isodose line. A restaging FDG-PET/CT scan demonstrated multiple metastases in the right and left hepatic lobes, left iliac external lymph nodes, left deep inguinal nodes, left distal thigh, left popliteal fossa, left anterior tibialis muscle, and right femur. Eleven days following SRS, he presented to the Emer- gency Department with weakness in his left upper extremity. An MRIrevealedanintervalincreaseinall brainlesions. eTh rightoccipitallobelesionmeasured2.4cm whilethe left frontal lobe lesion measured 1 cm in greatest diameter. High dose steroids were prescribed as the interval increase in all brain lesions was likely a result of post-SRS inflammation and not true progression of underlying disease. Interval MRI scans over the next 6 months showed stabilization of brain metastases while interval FDG-PET/CT imaging showed stabilization or complete resolution of extracranial lesions. Seven months aer ft completion of SRS, a single new brain metastasis was seen in the left supramarginal Figure 1: T1-postcontrast MRI showing a 2.7 × 3.5 × 3.1 cm gyrusand wastreated usingSRS 2000cGytothe 73%isodose hemorrhagic mass involving the right precentral gyrus. Following line in a single fraction. Representative pretreatment and 8- surgical resection, pathology confirmed metastatic melanoma. month posttreatment MR imaging are shown in Figure 2. At the time of paper preparation the patient is nine months post-surgery after resection of his rfi st brain metas- compared to SRS alone [8]. However, little has been reported tasis. He has remained on efavirenz/emtricitabine/tenofovir, about this treatment combination in patients with HIV. Here, though his adherence to the HAART therapy has been poor. we report our experience treating a patient with HIV and 3 His absolute CD4 counts have ranged from 126 to 449/mm multiple brain metastases with ipilimumab and concomitant with an undetectable viral load. He is able to function at his SRS. baseline. He experienced only minor gastrointestinal discom- fort throughout his treatment with ipilimumab and SRS. His extracranial metastases have remained stable or resolved. 2. Case Report A 48-year-old Caucasian male was diagnosed with HIV- 3. Discussion AIDS in 2009 aer ft presenting with oral candidiasis. His absolute CD4 count was 38/mm with a viral load of In our patient, the administration of SRS and ipilimumab was 176,000 copies/mL. He began highly active antiretroviral well tolerated and caused signica fi nt regression of widespread therapy (HAART) with efavirenz/emtricitabine/tenofovir melanoma metastases. Although the benefit of combinatorial (Atripla, Bristol-Myers Squibb). Also present at the time of therapy in this particular patient is unclear, synergy has been presentation was a melanoma on the right cheek, which was observed in animal models and human trials, suggesting subsequently excised. Due to neuropathy, the patient was that treatment approaches involving multiple mechanisms unable to tolerate lymphoscintigraphy, preventing sentinel of action may be more likely to overcome an immunosup- node localization. pressive tumor microenvironment than monotherapy [9]. Two years later, he experienced progressive, left-sided Knisely and colleagues reported in one retrospective study facial, upper extremity, and lower extremity numbness and that patients who received ipilimumab in combination with weakness. MRI of the head and spine revealed a hemorrhagic radiotherapy had a median survival of 21.3 months as com- mass involving the right precentral gyrus measuring 2.7× 3.5 pared to 4.9 months for patients who received radiotherapy × 3.1 cm with surrounding vasogenic edema (Figure 1). He alone [8]. In a prospective, randomized controlled trial, was admitted to Johns Hopkins Hospital and underwent a ipilimumab combined with dacarbazine improved overall craniotomy for tumor resection. Pathologic evaluation con- survival compared to dacarbazine alone in patients with firmed metastatic melanoma. metastatic melanoma [10]. Three weeks aeft r surgery, he began treatment with Reports describing HIV-positive patients with metastatic ipilimumab, administered at the standard dose of 3 mg/kg melanoma treated with immunotherapy are limited. of body weight every three weeks for four doses. One week Interleukin-2 was tested as an adjuvant to HAART therapy in following the first dose of ipilimumab, he received an SRS an attempt to stimulate antitumor activity but did not show a boost to the tumor bed of 2100 centigray (cGy) in 3 fractions survival benefit in a single patient [ 11]. Burke and colleagues prescribed to the73% isodoselineusing Cyberknife.Atthe reported on a single patient with HIV and stage IV melanoma time of the planning MRI, two more brain metastases were who was treated with ipilimumab and experienced disease noted: one in the right occipital lobe and another in the left regression without dose-limiting toxicities [12]. frontal lobe, each measuring 7 mm in greatest diameter. Both Preclinical studies describing the role of immune check- were treated with SRS 2000 cGy in a single fraction to the 73% point molecules, such as CTLA-4, in HIV pathogenesis Case Reports in Oncological Medicine 3 Radiation + ipilimumab Post Pre Right precentral gyrus mass (postsurgical resection) Radiation + Ipilimumab Left frontal middle gyrus mass Right medial occipital lobe mass Figure 2: T1-postcontrast MRI showing pretreatment (left column) and 8-month posttreatment (right column) MR imaging of melanoma brain metastases treated with SRS and ipilimumab. have also been revealing. One group has reported increased multiple systemic metastases. Although the contribution of viral replication following blockade of CTLA-4 in primates each therapeutic modality is unknown, a synergy reminiscent [13]. Studies of HIV-specific T cells demonstrate expression of the abscopal eeff ct is possible. eTh abscopal eeff ct describes of programmed death-1 (PD-1), another checkpoint mole- a phenomenon wherein a single lesion is irradiated, causing cule, which is associated with T cell exhaustion and progres- regression of distant metastases. While the exact mechanism sion of HIV [14]. Blocking the immunoregulatory pathway remains to be elucidated, the improvement in systemic met- comprisedofeitherCTLA-4orPD-1anditsligandsmayrein- astases is likely immune mediated. Lugade et al. reported vigorate a host immune response against a chronic infection that melanoma-bearing mice that had been irradiated had such as HIV. improved antigen presentation and an increase in interferon- Follow-up FDG-PET/CT imaging of our patient aer ft gamma secreting CD8+ cells aeft r peptide stimulation [ 15]. ipilimumab and SRS showed stabilization or regression of Similarly, in a single patient case report, Stamell et al. 4 Case Reports in Oncological Medicine reported the resolution of systemic melanoma metastases patient with HIV with metastatic melanoma,” Journal of Clinical Oncology,vol.29, no.32, pp.e792–e794,2011. and a greater-than-7-year survival in a patient treated with intracranial radiation in combination with ipilimumab [16]. [13] V.Cecchinato, E. Tryniszewska,Z.M.Maetal.,“Immune acti- vation driven by CTLA-4 blockade augments viral replication Based on our patient’s experience and the few cases at mucosal sites in simian immunodeficiency virus infection,” reported in the medical literature, further evaluation of the Journal of Immunology, vol. 180, no. 8, pp. 5439–5447, 2008. benefit of radiotherapy and immunotherapies such as ipili- [14] C. L. Day, D. E. Kaufmann, P. Kiepiela et al., “PD-1 expression mumab to patients with metastatic melanoma and underlying on HIV-specific T cells is associated with T-cell exhaustion and HIV infection is warranted. Outcomes of interest include disease progression,” Nature,vol.443,no. 7109,pp. 350–354, tumor response to therapy, eeff ct on CD4 count and viral load, and changes in function of HIV-specific T cell function. [15] A. A. Lugade, J. P. Moran, S. A. Gerber, R. C. Rose, J. G. Frelinger, and E. M. Lord, “Local radiation therapy of B16 mel- References anoma tumors increases the generation of tumor antigen-speci- fic effector cells that traffic to the tumor,” Journal of Immunology, [1] M. J. Silverberg, C. Chao, W. A. Leyden et al., “HIV infection, vol. 174, no.12, pp.7516–7523,2005. immunodeficiency, viral replication, and the risk of cancer,” [16] E. F. Stamell, J. D. Wolchok, S. Gnjatic, N. Y. Lee, and I. Brownell, Cancer Epidemiology Biomarkers and Prevention,vol.20, no.12, “eTh Abscopal eeff ct associated with a systemic anti-melanoma pp. 2551–2559, 2011. immune response,” International Journal of Radiation Oncology, [2] L.K.Rodrigues,B.J.Klencke,K.Vin-Christianetal., Biology, Physics, vol. 85, no. 2, pp. 293–295, 2013. “Altered clinical course of malignant melanoma in HIV-positive patients,” Archives of Dermatology,vol.138,no. 6, pp.765–770, [3] F.S.Hodi, S. J. O’Day, D. F. McDermottetal.,“Improved sur- vivalwithipilimumabinpatientswithmetastaticmelanoma,” New England Journal of Medicine,vol.363,no. 8, pp.711–723, [4] K. Margolin, M. S. Ernstoff, O. Hamid et al., “Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial,” The Lancet Oncology ,vol.13, no.5,pp. 459–465, [5] J. S. Weber, A. Amin, D. Minor, J. Siegel, D. Berman, and S. J. O’Day, “Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial,” Melanoma Research,vol.21, no.6,pp. 530– 534, 2011. [6] Q.Leng, Z. Bentwich,E.Magen,A.Kalinkovich,and G. Borkow, “CTLA-4 upregulation during HIV infection: associ- ation with anergy and possible target for therapeutic interven- tion,” AIDS,vol.16, no.4,pp. 519–529, 2002. [7] J.L.Riley,K.Schlienger, P. J. Blairetal.,“Modulation of sus- ceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule,” Journal of Experimental Medicine,vol.191,no. 11, pp.1987–1997,2000. [8] J.P.Knisely,J.B.Yu, J. Flanigan,M.Sznol,H.M.Kluger, andV. L. Chiang, “Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival,” Journal of Neurosurgery,vol.117,no. 2, pp.227–233,2012. [9] J.L.Frazier,J.E.Han,M.Lim, andA.Olivi,“Immunotherapy combined with chemotherapy in the treatment of tumors,” Neurosurgery Clinics of North America,vol.21, no.1,pp. 187–194, [10] C. Robert,L.Thomas,I.Bondarenkoetal.,“Ipilimumab plus dacarbazine for previously untreated metastatic melanoma,” New England Journal of Medicine,vol.364,no. 26,pp. 2517– 2526, 2011. [11] C. Hoffmann, H. A. Horst, M. Weichenthal, and A. Hauschild, “Malignant melanoma and HIV infection—aggressive course despite immune reconstitution,” Onkologie,vol.28,no.1,pp.35– 37, 2005. [12] M. M. Burke, H. M. Kluger, M. Golden, K. N. Heller, A. Hoos, and M. 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