1. Management of Immune- related adverse events and kinetic of response withTargeted Therapy Ahmed Allam A.H. Mohammed.Ass. Lecturer, Clinical oncology and Nuclear med. Depart. AssiutUniversity Hospitals

2. Targeted Therapy ?* normal cells, the pathways that control cell growth, death, and differentiation are regulated byIn communication within the cell, called signal transduction, and by signals that pass from one cell to another. cancer cell, these regulatory mechanisms are bypassed, so the cells avoid cell death and demonstrate In uncontrolled growth and impaired differentiation.Growing tumors associated with neovascularization and evading the immune systemTargeted therapy refers to a growing class of agents that target molecular pathways that are known to be altered in cancer cells and micor-enviroment.Chabner BA, Barnes J, Neal J, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman &Gilmans The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011:1731-1753. 3. Click to edit Master text stylesSecond level Third level Fourth level Fifth levelUnlike chemotherapy, which often destroys both normal and cancer cells,targeted therapy selectively inhibits the pathways cancer cells rely on to growand survive and may kill or arrest the growth of cancerous cells while sparingmost normal cells. 4. Main Categories of Targeted Therapy 1- Small Molecules: Selective hormonal receptor modulator: Tamoxfien. Tyrosine Kinase inhibitors: Imatinib mesylate,Erlotinib. Apoptosis-inducedproteasome inhibitor:Bortezomib. PARP inhibitors: Olaparib, Iniparib. 5. Main Categories of Targeted Therapy( contd).2- Monoclonal antibodies I-according to type of mAb MurinemAb:(suffix-momab)highly immunogenicExample: Ibritumomab. Chimeric mAb: (suffix-ximab) murine variable region fused onto constant human constant region 65% human. Example: Rituximab. Humanized mAb: (suffix-zumab) murine hypervariable fused into human antibody95% human. Example: Bevacizuman. Human mAb: (suffix-mumab) transfer the human Ig genes into murine genome, then the mouse is vacinated against the desire antigenfull human in vitro Ab. Example: Panitumumab. 6. Main Categories of Targeted Therapy( contd).2- Monoclonal antibodies (contd) II- according to the target Target tumor (suffix-tu**mab) Example Cetuximab. Target cardiovascular system (suffix-ci**mab) Example: Bevacizuman. Target immune system (suffix-li**mab) Example Ipilimumab, Termelimumab 7. Ipilimumab* and TremelimumabBoth are anti CTLA-4 antibodies.CTLA-4 is one of two homologous proteins present within T-cells that are exported to the cell surface after immune cellactivation and counterbalance each other in the stimulationand inhibition of T cell proliferation and activation.CTLA-4, which has a much greater binding affinity for the B7surface molecules found on the antigen-presenting cell (APC)than CD28, effectively induces T cell anergy and inhibits cellproliferation and secretion of IL-2.In contrast, its counterpart, CD28, is a costimulator of T cellproliferation and the production of IL-2*Ipilimumab: controversies in its development, utility and autoimmune adverse events. Weber J, Cancer Immunol Immunother (2009) 58:823830 DOI10.1007/s00262-008-0653-8 8. Ipilimumab and Tremelimumab (contd) Click to edit Master text stylesSecond level Third level Fourth level Fifth level*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and AxelHauschild VOLUME JULY 20 2012 9. Ipilimumab (Yervoy)Click to edit Master text styles Second level Third level Fourth level Fifth level 10. Ipilimumab (Yervoy)A total of 676 patients with unresectable stage III or IVmelanoma, were randomly assigned, in a 3:1:1 ratio, toreceive ipilimumab plus gp100 (403 patients),ipilimumab alone (137), or gp100 alone (136).Ipilimumab, at a dose of 3 mg per kilogram of bodyweight, was administered with or without gp100 every 3weeks for up to four treatments (induction). Eligiblepatients could receive reinduction therapy. The primaryend point was overall survival.**Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. F. Stephen Hodi, M.D.,et al., n engl j med 363;8 august 19,2010. 11. Ipilimumab (Yervoy) contd Overall survival rate at 1 year was 46% (95% CI: 37.0, 54.1) in the Ipilimumab arm vs25% (95% CI: 18.1, 32.9) in the gp100 arm.* Overall survival rate at 2 years was 24% (95% CI: 16.0, 31.5) in the Ipilimumab armvs 14% (95% CI: 8.0, 20.0) in the gp100 arm.* Median overall survival in the Ipilimumab + gp100 arm was 10 months (95% CI: 8.5,11.5), 6 months (95% CI: 5.5, 8.7) in the gp100 arm, and 10 months (95% CI: 8.0, 13.8)in the Ipilimumab arm.* Click to edit Master text stylesSecond level Third level Fourth level Fifth level*Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. F. Stephen Hodi, M.D.,et al., n engl j med 363;8 august 19, 2010. 12. Ipilimumab (Yervoy) contdAssociated with unique side effects of the drug called immune-related adverse events irAEs.Unique kinetic of response. 13. Immune-related Adverse Events irAEsEarly in ipilimumabs development, it became clear that it induced dose-related, immune- related, or inflammatory side effects.* The most common systems affected were the skin, gut, liver, and pituitary. *Immunohistochemistry of affected skin and gut revealed infiltration by CD4 and CD8 T- cells, and highly activated effector cells correlated with side effect intensity.*Elevated inflammatory cytokines in the sera, as well as rapid resolution of some irAE symptoms with use of the tumor necrosis factor-alpha antibody infliximab, suggested that cytokine release by activated T cells was associated with irAEs*Drug-related overall adverse events were observed in 84.6% of patients, of which immune- related adverse events of any grade accounted for 72.3%.***Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma andovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100:4712-4717.**Lebbe C, ODay S, Chiarion Sileni V, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients withmetastatic melanoma. Presented at Perspectives in Melanoma XII, The Hague, Netherlands, October 2-4, 2008. 14. Immune-related Adverse Events irAEs(contd)Dermatologic Toxicity:A diffuse, erythematous maculopapular rash that can be intensely pruritic was observed in 47% to 68% of patients, starting an average of 3 to 4 weeks after ipilimumab.*In 4% of patients, it was severe.*Rare cases of toxic epidermal necrolysis, as well as Stevens-Johnson syndrome, both in less than 1% of patients, have been reported with ipilimumab, and several patients with those conditions have died *Microscopic examination shows a perivascular lymphocytic infiltrate that extends deep into the dermis in most cases.**Immunohistochemical staining showed that CD4-positive and Melan-A-specific CD8- positive T cells were in close proximity to apoptotic melanocytes, suggesting that an immune response was directed against melanocytes, This is consistent with a reported 11% rate of vitiligo with ipilimumab.***Weber J. Ipilimumab: Controversies in its development, utility, and autoimmune adverse events. Cancer Immunol Immunother. 2009;58:823-830.**Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma andovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100:4712-4717. 15. Dermatologic Toxicity (contd):*Topical glucocorticosteroids (e.g., betamethasone 0.1% cream) or urea-containing creams in combination with oral antipruritics (e.g.,diphenhydramine HCl or hydroxyzine HCl) are recommended for G1-2.For G 3 dermatologic irAEs, one should hold a dose and treat with a 3 to4-week tapering course of oral steroids, starting at 1 mg/kg prednisoneor dexamethasone 4 mg four times orally daily.Ipilimumab can be held for moderate to severe skin toxicity but shouldbe permanently discontinued for severe, life-threatening skin toxicityand steroids initiated at 1 to 2 mg/kg prednisone orally or its equivalenttapering over not less than 30 days.*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and Axel Hauschild VOLUME JULY 202012 16. Immune-related Adverse Events irAEs(contd)Diarrhea/ColitisGI and hepatic adverse events began to occur within 6 to 7 weeksDiarrhea occurs in up to 44% of patients receiving Ipilimumab at dose of 10 mg/kg.*Severe diarrhea (grade 3 or 4; at least six diarrheal bowel movements above baseline in 24 hours) was reported in approximately 18% of patients.*Diarrhea can also be associated with signs and symptoms of colitis, which can lead to obstruction and bowel perforation, potentially requiring colostomy. The rate of bowel perforation is less than 1%.*IrAE-related colitis involves the descending colon more often than the sigmoid colon, ascending colon, or rectum.** *Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517- 2525, 2011 ** Wolchok JD, Neyns B, Linette G, et al: Ipilimumab monotherapy in patients with pretreated advanced melanoma: A randomised, double- blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11:155-164, 2010 17. Diarrhea/Colitis (cond):*Low-grade diarrhea (grade 1, an increase of 2 over baseline in 24hours) should be treated symptomatically using loperamide, oralhydration, and electrolyte substitution.With persistent or higher-grade diarrhea, bacterial or parasiticinfection, viral gastroenteritis, or the first manifestation of an IBDmust be ruled out by examination for stool leukocytes, stool cultures,and a Clostridium difficile titer.Grade 2 diarrhea can be treated with the addition of oraldiphenoxylate hydrochloride and atropine sulfate four times daily.Endoscopy is recommended to confirm or rule out colitis withpersistent grade 2 diarrhea or grades 1 to 2 diarrhea with bleeding.*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and Axel Hauschild VOLUME JULY 202012 18. Diarrhea/Colitis (cond):* For grade 3 or 4 diarrhea (7 or more increase over baseline in 24 hours), treatment with ipilimumab should be permanently discontinued and intravenous steroids and replenishment of fluid and electrolytes intravenously should be instituted. Intravenousmethylprednisolone 125 mg should be given. Oral dexamethasone 4 mg every four hours or prednisone 1 to 2 mg/kg/daily can be given thereafter, followed by a taper and discontinuation over the next 6 weeks. If intravenous steroids followed by high-dose oral steroids does not decrease symptoms within 48 to 72 hours,treatment with infliximab at 5 mg/kg every 2 weeks is an alternative. Once relief of symptoms is achieved, which can be very rapid and dramatic, it should be discontinued and a prolonged steroid taper over 45 to 60 days should be instituted.*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and Axel Hauschild VOLUME JULY 202012 19. Click to edit Master text styles Second level Third level Fourth level Fifth level71-year-old woman receiving ipilimumab for treatment of metastatic melanoma.Axial CT image of pelvis shows mural thickening of sigmoid colon with adjacent fatstranding and mesenteric hypervascularity. Colonic biopsy revealed moderate-to-severe active inflammation, consistent with ipilimumab-induced colitis.Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241W246 20. Immune-related Adverse Events irAEs (contd)Hepatotoxicity:Immune-related hepatotoxicity was observed in 3% to 9% ofpatients receiving anti-CTLA-4 antibodies.***It usually presents as an asymptomatic increase of transaminasesand bilirubin, although some patients also have fevers and malaise.Liver biopsies have shown a diffuse T-cell infiltrate consistent withimmune-related hepatitis.This must be differentiated from progressive metastases in the liver,as well as other etiologies such as viral hepatitis or another drug-specific toxic reactions.*Hodi FS, ODay SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010** Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-2525,2011 21. Hepatotoxicity (contd):*One should perform a standard workup to rule out viral hepatitis, disease progression, and other drug-related causes for abnormal liver functions.The current algorithm for the management of a hepatotoxicity irAE contains the recommendation that for grades 3 to 5 toxicity, one should use high-dose intravenous glucocorticosteroids for 24 to 48 hours, followed by an oral steroid taper with dexamethasone in a dosage of 4 mg every 4 hours or prednisone at 1 to 2 mg/kg tapered over not less than 30 days.If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, consideration should be given to the use of oral mycophenolate mofetil 500 mg every 12 hoursInfliximabbecause of its potential for hepatotoxicityshould be avoided in this setting.*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and AxelHauschild VOLUME JULY 20 2012 22. Click to edit Master text styles Second level Third level Fourth level Fifth level 59-year-old man with metastatic melanoma undergoing treatment with ipilimumab. A, Baseline CT image obtained before treatment shows normal appearance of liver. B, Repeat CT image obtained 8 weeks after commencing treatment because of elevated liver function test levels shows diffusely decreased attenuation of hepatic parenchyma and new periportal edema (arrow). Liver biopsy showed severe active hepatitis consistent with drug-induced cause.Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241W246 23. Immune-related Adverse Events irAEs(contd) Hypophysitis :* Immune-related hypophysitis occurs in 1% to 6% of patients treated with 3 or 10 mg/kg ipilimumab. Headache,nausea, vertigo, behavior change, visual disturbances such as diplopia, and weakness occur at an average of 6 weeks after initiation of therapy. The most important differential diagnosis is the new occurrence of brain metastases. Magnetic resonance imaging scans with gadolinium and selective cuts of the pituitary can show enlargement or heterogeneity and confirm the diagnosis* Blansfield JA, Beck KE, Tran K, et al: Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients withmetastatic melanoma and renal cancer. J Immunother 28:593-598, 2005 24. Hypophysitis (contd):* Before treatment, a blood sample should be taken todetermine pituitary, thyroid, adrenal, and gonadalstatus (serum morning cortisol, adrenocorticotropichormone [ACTH], free triiodothyronine [T3], freethyroxine [T4], thyroid-stimulating hormone [TSH]and,in addition, testosterone in males and folliclestimulating hormone, luteinizing hormone, andprolactin in females). Typically, low levels of thyroid, adrenal, and gonadalhormones are found, but they may all be reduced,only one axis may be decreased, or one may be spared.*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and AxelHauschild VOLUME JULY 20 2012 25. Hypophysitis (contd): * For symptomatic pan-hypopituitarism and for any grade 3 to 4endocrinopathy, the ipilimumab dose should be held, initial dose of methylprednisolone 1 to 2 mg/kg intravenously shouldAnbe given. This should be followed by prednisone 1 to 2 mg/kg, orally onceper day with gradual tapering over 4 weeks and replacement ofappropriate hormones as the steroid dose is tapered. Usually, after a fewdays, symptoms improve, and a reduction of the swelling andheterogeneity of the pituitary gland can be observed radiologically. Consultation with an endocrinologist is appropriate for furthermanagement.*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and AxelHauschild , JCO, VOLUME JULY 20 2012 26. Click to edit Master text stylesSecond level Third level Fourth level Fifth levelPituitary enlargement. (A) Magnetic resonance imaging scan of the brain withpituitary cuts performed pretreatment on June 30, 2004; (B) same cut afterdevelopment of hypopituitarism with an enlarged and inhomogeneouspituitary on December 3, 2004.* Blansfield JA, Beck KE, Tran K, et al: Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients withmetastatic melanoma and renal cancer. J Immunother 28:593-598, 2005 27. Click to edit Master text stylesSecond level Third level Fourth level Fifth level Kinetics of appearance of Immune-Related Adverse Events**Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and AxelHauschild , JCO, VOLUME JULY 20 2012 28. Immune-related Adverse Events irAEs(contd) Pancreatitis: * Immune-related pancreatitis has been reported in less than 1.5% of patients receiving anti-CTLA-4 antibodies. This generally manifested as an asymptomatic increase of amylase and lipase, although some patients also had accompanying fevers and malaise. Nausea and vomiting were rare, although abdominal pain was frequent, often low grade, and out proportion to the degree of increase in the results of blood tests. An oral steroid taper with prednisone or dexamethasone was indicated, but often this had minimal immediate effects on the biochemical abnormalities that resolve slowly.*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and AxelHauschild , JCO, VOLUME JULY 20 2012 29. Immune-related Adverse Events irAEs(contd) Neuropathies:* Transient peripheral neuropathies, both sensory and motor, have been reported in lessthan 1% of patients. In some cases, they were minor and simply resolved spontaneously. One can hold a dose of ipilimumab in patients with persistent grade 2 neuropathy that isnot interfering with daily activities. Persisting and worsening neuropathies should betreated with an oral steroid taper with prednisone or dexamethasone of 3 to 4 weeks. For severe (grade 3 and 4) neuropathies, ipilimumab should be permanently discontinued,and one should initiate systemic corticosteroids at a dose of prednisone or equivalent 1 to 2mg/kg once per day, including tapering over at least 30 days*Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab, Jeffrey S. Weber, Katharina C. Kahler, and AxelHauschild , JCO, VOLUME JULY 20 2012 30. Unique Kinetic of Response.The first response criteria for solid tumors were developed approximately 30 years ago by the World Health Organization (WHO).*More recently, these criteria have been superseded by the Response Evaluation Criteria in Solid Tumors (RECIST) published in 2000**, and updated in 2009 (RECIST 1.1)***.Using the latter criteria, early increases in tumor size or the appearance of new lesions is classified as progressive disease, a term now synonymous with treatment failure***.Frequency of tumour re-evaluation while on treatment should be protocol specific and adapted to the type and schedule of treatment. However, in the context of phase II studies where the beneficial effect of therapy is not known, follow-up every 68 weeks***. *Reporting results of cancer treatment. Miller AB, Hoogstraten B, Staquet M, Winkler A.. Cancer 1981; 47:207214 **New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205216 ***New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), EUROPEAN JOURNAL OF CANCER 4 5 ( 2 0 0 9 ) 2 2 8 2 4 7 31. Unique Kinetic of Response (cond) Hamid et al.* undertook a review and analysis of five studies on 269 patients with stage III or IV melanoma to determine the kinetics and duration of response with ipilimumab. An objective response was observed in 41 patients (15%). Some patients had a late onset CR or PR occurring, at 10106 weeks and 562 weeks after treatment initiation, respectively. In 28 patients, onset of response occurred after more than 12 weeks of treatment, and in 4 patients, PD preceded a response without additional therapy. In some patients, PD was followed by SD, and ultimately, PR. The duration of response has been considerable as well, with the overall response duration ranging from 6 to 187 weeks. Late-onset response was not associated with dose, regimen or concomitant therapy.*Hamid O, Urba WJ, Yellin M et al (2007) Kinetics of response to ipilimumab (MDX-010) in patients with stage III/IV melanoma. J Clin Oncol suppl 25: abstr 8525 32. Unique Kinetic of Response (cond)Immune-related response criteria were proposed by a collaborative group of approximately 200 oncologists, immunotherapists, and regulatory experts who convened in 2004 and 2005 to devise these criteria on the basis of clinical observations*.These criteria were validated using a series of large multinational studies including 487 patients treated with ipilimumab*.*Wolchok JD, Hoos A, ODay S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res 2009; 15:74127420 33. Patterns of Tumor Response to Ipilimumab*:Response to treatment with ipilimumab can be complete (immune- related complete response) or partial (immune-related partial response).Four distinct patterns of tumor response to ipilimumab have been described :1. type A, reduction in size of baseline lesions with no new lesions;2. type B, stable disease with no significant change in the sizeof the baseline lesions that may or may not be followed by a slow, steady decline in tumor size;3. type C, initial increase in tumor burden followed by response; and4. type D, reduction in total tumor burden in spite of the appearance of new lesions.*Wolchok JD, Hoos A, ODay S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res 2009; 15:74127420 34. Patterns of Tumor Response to Ipilimumab: Click to edit Master text stylesSecond level Third level Fourth level Fifth level 35. Click to edit Master text styles Second level Third level Fourth level Fifth level Type A response to ipilimumab therapy in 55-year-old man with metastatic melanoma to right thigh and lung. A and B, Baseline CT images obtained before treatment show large mass in anterior compartment of right thigh (arrow, A) and right lower lobe pulmonary nodule (arrow, B). C and D, CT images obtained 12 weeks after commencing treatment with ipilimumab show significant reduction in size of right thigh mass (arrow, C) and interval resolution of right lung nodule.Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241W246 36. Click to edit Master text styles Second level Third level Fourth level Fifth levelType B response to ipilimumab therapy in 71-year-old woman with metastaticmelanoma to lung. A, Baseline CT image obtained before treatment showslobulated nodule (arrow) in right middle lobe. B, Repeat CT image obtained 12weeks after commencing ipilimumab therapy shows no significant change in size ofnodule (arrow), indicating stable diseaseRadiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241W246 37. Click to edit Master text styles Second level Third level Fourth level Fifth levelType C response to ipilimumab therapy in 56-year-old woman with metastaticmelanoma to both lower extremities. A, Lower extremity coronal reformatted CTimage shows multiple bilateral masses in medial compartments of both thighs (arrowand arrowhead). B, Repeat CT image obtained 12 weeks after commencingipilimumab therapy shows interval enlargement of masses (arrow and arrowhead). C,Repeat CT image at 24 weeks shows significant response. Arrow and arrowheadpoint to areas where masses shown in A and B were.Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241W246 38. Click to edit Master text styles Second level Third level Fourth level Fifth level Type D response to ipilimumab therapy in 56-year-old woman with metastatic melanoma. A and B, CT images obtained at baseline (A) and 12 weeks after commencing ipilimumab therapy (B) show new subcutaneous nodule in left gluteal region (arrow, B), considered suspicious for new melanoma deposit; other new subcutaneous nodules were also seen. C, Repeat CT image obtained at 24 weeks shows complete resolution of nodule. Other target lesions in same patient also showed response to treatment.Radiologic Aspects of Immune- Related Tumor Response Criteria and Patterns of Immune-Related Adverse Events in Patients Undergoing Ipilimumab Therapy, AJR 2011; 197:W241W246 39. Click to edit Master text styles Second level Third level Fourth level Fifth level 40. Science and Charityone of the major works from Picassos early years. At just 15, Picasso felt mature enough to take onlarge ambitious compositions as the culmination of his academic studies in Barcelona School of FineArts that were led by his father Jose Ruiz Picasso, who was the model for the doctor in this painting.