Wolfram Samlowski | University of Nevada, Reno (original) (raw)
Papers by Wolfram Samlowski
Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell ... more Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n ¼ 10) or without (n ¼ 3) prior cryopreservation. Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457-65. Ó2014 AACR.
Cancers, Jan 30, 2024
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Clinical Oncology, Oct 1, 2005
Familial melanoma patients are reported to present with thinner melanomas, to be younger at the t... more Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma. Patients and Methods This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk. Results Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P ϭ .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P Ͻ .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P ϭ .2). Conclusion These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.
Haemophilia, Nov 1, 1999
The effects of a recombinant factor IX product (BeneFix), and of five plasma‐derived factor IX pr... more The effects of a recombinant factor IX product (BeneFix), and of five plasma‐derived factor IX products, AlphaNine, Immunine, Konyne, Mononine and Replinine on in vitro peripheral blood mononuclear cell (PBMC) immune function were compared in a blinded study. We assessed the effects of these products on Con‐A‐induced lymphocyte proliferation and interleukin‐2 and interleukin‐10 secretion, expression of lymphocyte activation markers, and nitric oxide secretion by stimulated mouse peritoneal macrophages. At 1 mL–1 for 48 h, Konyne reduced Con‐A‐induced mitogenesis by 50% (P < 0.05); AlphaNine, Mononine and BeneFix had no effect. At 10 IU mL–1, Con‐A‐induced mi‐ togenesis was at control levels with Mononine and BeneFix, but was reduced to <15% (P < 0.05) with each of the other products. IL‐2 and IL‐10 secretion by Con‐A‐stimulated lymphocytes was also markedly depressed by all the products tested except Mononine and BeneFix. Dialysis of these products did not substantially affect these results. Flow cytometric analysis of lymphocyte activation markers following Con‐A stimulation showed that Konyne also decreased IL‐2 receptor α and β chain (CD25 and CD122) induction on PBMC. Konyne also inhibited nitric oxide secretion to levels <18% of controls. These results indicate that certain factor IX products, including some of purported higher purity, substantially depress in vitro immune function. The importance of these findings to in vivo immune function in haemophilia B patients remains to be established.
Journal of The National Comprehensive Cancer Network, Mar 31, 2023
Annals of case reports, Jul 18, 2022
Introduction: Checkpoint inhibitor (CKI) therapy has markedly altered the survival of patients wi... more Introduction: Checkpoint inhibitor (CKI) therapy has markedly altered the survival of patients with many solid tumors. It appears clear that 10-40% of patients with a number of metastatic cancers can achieve lengthy remissions following CKI therapy. The optimal duration of treatment or whether treatment can ever be safely stopped is still controversial. Based on melanoma-derived data, we tested whether CKI treatment could safely be discontinued in patients with other solid tumors. Methods: A retrospective analysis was performed in adults with metastatic solid tumors treated with CKI-based therapy. Patients with solid tumors who achieved complete remission on 2 sequential scans at least 3 months apart during ongoing treatment were identified from our computerized patient database. Patient data was analyzed for patient characteristics, as well as progression-free and overall survival. Results: A total of 69 non-melanoma solid tumor patients were treated with CKI-based regimens in our clinic and 14 achieved complete remission (20.3%). Five patients were female (35.7%) and the remaining nine were male (64.3%). A 100% progressionfree survival was observed for these patients. The median duration of complete remission was over 20 months from the time of elective treatment discontinuation. Median overall survival was not reached in this cohort. One patient died of non cancerrelated causes. Conclusions: Based on this retrospective case series, elective treatment discontinuation in patients who achieved complete remission appears feasible. All patients remained in a durable complete remission after treatment discontinuation. We hypothesize that appropriate selection of patients for early treatment discontinuation may decrease their economic burden related to ongoing treatment, limit potential toxicity, and improve quality of life.
Research Square (Research Square), Apr 5, 2021
Background: Virtually all metastatic melanoma patients who progress after initial treatment with ... more Background: Virtually all metastatic melanoma patients who progress after initial treatment with PD-1 or CTLA-4 directed antibodies will die of their disease. Salvage options are urgently needed. It is theoretically attractive to combine immunotherapy with targeted agents in progressing patients with BRAF mutation positive melanoma, but the toxicity of combined treatment has proven challenging. We have observed striking responses with the cautious addition of low doses of targeted therapy to PD-1 antibody treatment at the time of disease progression following initial immunotherapy. This allowed conversion of a signi cant number of rapidly progressing patients to durable complete responses in BRAF mutant melanoma. Results: We therefore performed a retrospective analysis of our large patient database and identi ed 23 patients who progressed on initial checkpoint inhibitor treatment, who subsequently had cautious addition of BRAF±MEK inhibitor therapy to PD-1 antibody treatment. We found an objective response rate of 55% in second line therapy, with a median progression-free survival of 33.4 months and median overall survival of 34.1 months, with 40% of patients in remission over 3 years. Ten of 12 responding patients were able to discontinue all therapy and continue in unmaintained remission. Toxicity of this approach was generally manageable (only 21.7 % grade 3-5 toxicity). There was 1 early sudden death for unknown reasons in a responding patient. Conclusions: Our results suggest that 2 nd line therapy with PD-1 inhibitors plus BRAF±MEK inhibitors has substantial activity and manageable toxicity. This treatment can induce additional durable complete responses after failure of initial immunotherapy of metastatic melanoma. These remarkable results suggest further evaluation be performed of sequential checkpoint inhibitor therapy with cautious addition of targeted therapy in appropriate patients.
Drs. Rini and Bukowski do an excellent job of updating and commenting on the rapidly evolving fie... more Drs. Rini and Bukowski do an excellent job of updating and commenting on the rapidly evolving field of therapy for metastatic renal cell carcinoma (RCC).
Modecular medicine and medicinal, Oct 1, 2010
American Journal of Roentgenology, Oct 1, 1997
H igh-dose interleukin-2 (IL-2)-based treatment induces objective regressions in l3 35% of patien... more H igh-dose interleukin-2 (IL-2)-based treatment induces objective regressions in l3 35% of patients with metastatic or unresectable renal cell carcinoma, with 3-I 1% complete responses [1]. In many other patients. IL-2 immunotherapy induces prolonged disease stabilization. Thus, on radiography. residual abnormalities after treatment may represent viable, but quiescent, tumor that will eventually progress. Alternatively, studies such as chest radiography, CT. and MR imaging may underestimate treatment responses. Furthermore,
Frontiers in oncology, Mar 14, 2024
Mucosal melanoma represents an uncommon melanoma subtype. Wide excision has long represented the ... more Mucosal melanoma represents an uncommon melanoma subtype. Wide excision has long represented the standard therapeutic approach. Unfortunately, there is a high relapse rate and mortality. Neoadjuvant therapy with ipilimumab plus nivolumab has shown significant activity in cutaneous melanoma. We present two cases of mucosal melanoma, each with potential regional dissemination, who were treated with neoadjuvant immunotherapy with minimal toxicity. Both patients were closely monitored and achieved radiologic and pathologic complete responses. These patients were able to avoid radical surgery and related functional consequences. Both patients remain recurrence-free with protracted follow-up. The potential usefulness of neoadjuvant immunotherapy as an organ preservation strategy in mucosal melanoma deserves further evaluation in prospective clinical trials.
The Journal of Clinical Endocrinology & Metabolism, 1997
Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatmen... more Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatment, patients develop severe hypocholesterolemia along with striking alterations in the concentration and composition of the circulating lipoproteins. The present study was undertaken to gather information about the pathogenesis of these abnormalities. Patients were studied before-, during-and after a 5-day course of high dose iv rIL-2. Whole plasma cholesterol was markedly reduced by rIL-2 administration (52%; P Ͻ 0.001), whereas the triglyceride concentration did not change. Thus, the lipoproteins became triglyceride enriched (P ϭ 0.004). Low density lipoprotein cholesterol, apolipoprotein B (apoB), high density lipoprotein cholesterol, and apoA-I concentrations all decreased. Esterified cholesterol levels were markedly reduced. Total plasma apoE increased markedly, and two kinds of abnormal particles appeared: 1) -migrating, very low density lipoproteins; and 2) discoidal, apoE-and phospholipid-containing particles with abnormal density and electrophoretic mobility. The activities of two lipoprotein triglyceride hydrolases, lipoprotein lipase and hepatic lipase, fell significantly during treatment and returned promptly to pretreatment levels after rIL-2 was discontinued. Lecithin:cholesteryl acyltransferase (LCAT) activity also decreased significantly (64%) during treatment, but in contrast to the lipases, remained low for at least 5 days after the last dose of rIL-2 (P Ͻ 0.001). High dose iv rIL-2 induces severe dyslipidemia with deficiencies of both postheparin lipases and acute LCAT deficiency. Most, if not all, of the lipoprotein changes observed are explained by the LCAT deficiency that follows IL-2-induced hepatocellular injury and cholestasis.
Journal of Clinical Oncology, May 20, 2015
4565 Background: The aim of this study is to determine if achievement of stable disease as a best... more 4565 Background: The aim of this study is to determine if achievement of stable disease as a best response to HD IL-2 may improve survival outcomes. Recent data suggest that immunotherapy may improve survival even in those pts who do not experience objective responses (CR+PR). Methods: All sequential mRCC pts treated with HD IL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses to HD IL-2 were correlated with survival outcomes using landmark analysis at 2 months—the median time to first disease assessment. Results: A total of 391 pts (75% male; median age 55 yrs, range 13-77) were included and belonged to the following risk categories: 80 (20%) good, 251 (64%) intermediate, and 60 (15%) poor. A CR was identified in 35 (9%), PR in 39 (10%), SD in 125 (32%), progressive disease (PD) in 164 (42%), and not evaluable for response (NE) in 28 (7%) pts. Median OS for the favorable, intermediate and poor risk groups were 53.8 (p=0.0015 vs intermediate), 26....
Cancer Research, Apr 1, 2004
658 Selective expression of cytokines on the surface of tumors is likely to stimulate tumor-infil... more 658 Selective expression of cytokines on the surface of tumors is likely to stimulate tumor-infiltrating lymphocytes that are primed and already recognize tumor antigens. This may result in enhanced tumor recognition and killing. This gene therapy approach may avoid toxicity associated with systemic therapy with high doses of the cytokines needed to achieve the same effects. In order to test this concept, we have evaluated an IL-2 gene construct that is designed to induce tumor cells to express a membrane bound form of IL-2 (IL-2tm). A mammalian plasmid expression vector was designed to express a fusion gene consisting of human interleukin 2 with a Fc receptor epsilon transmembrane anchor derived from the gamma subunit of the Fc receptor epsilon. We demonstrated that mRNA and protein for the IL-2tm fusion protein was expressed in transfected RD995 tumor cells. Expression of the IL-2tm protein on the tumor cell surface membrane was confirmed by laser confocal microscopy. In order to assess biological function, RD995 transfected with IL-2tm or the empty expression vector (pCMV2b) were implanted subcutaneously into C3H/HEN mice. Non-transfected RD995 was also implanted subcutaneously for tumor growth comparison (control group). Groups of mice implanted with 10 6 or 10 5 RD995 transfected with IL-2tm grew considerably more slowly than RD995 transfected with pCMV2b or non-transfected control RD995 implanted tumors. Further preclinical evaluation of the IL-2tm gene therapy as a possible cancer treatment is underway.
Journal of Clinical Oncology, 2012
10614 Background: Identification of rare (>2-5) circulating tumor cells (CTC) in 7.5 ml blood ... more 10614 Background: Identification of rare (>2-5) circulating tumor cells (CTC) in 7.5 ml blood by immunofluorescence assay (IFA) correlates with a poor prognosis in colon, breast, prostate and lung cancer. Changes in CTC count during treatment also predict the eventual patient progression and survival in these cancers. Existing assays do not detect melanoma CTC, however. In addition, isolation of viable CTC remains problematic. To overcome these limitations we attempted to develop novel melanoma CTC assays, using IFA and cell culture approaches. Methods: Blood samples were obtained from patients and controls following informed consent. The buffy coat (white cells + tumor) was isolated by Ficoll/Hypaque centrifugation, and split into 6 replicate cultures in proprietary TrueCells medium. After 21 days in culture, tumor colonies were counted, and stained for melanoma and leukocyte markers. Buffy coat cells from parallel blood samples were stained with a panel of CSPG4-specific mAb (a...
Journal of Clinical Oncology, 2014
487 Background: HD IL-2 is associated with an objective response rate of 16-20% with durability o... more 487 Background: HD IL-2 is associated with an objective response rate of 16-20% with durability of response in select mRCC patients. HD IL-2 is also associated with significant toxicity including vascular leak syndrome and inflammatory side effects. Few predictive markers can identify patients likely to respond to HD IL-2. Methods: Patients treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 with clear cell mRCC were evaluated. Grade of toxicities during HD IL-2 treatment were collected based on provider documentation in the electronic health record. Rates of adverse events (AEs) and overall survival stratified grade 3 AEs were evaluated by Kaplan-Meier survival estimates and Cox proportional hazards models. All AEs were graded per common terminology criteria version 4. Grade 3 rigors were defined as severe rigors requiring opioids. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) ...
Journal of Clinical Oncology, 2014
460 Background: CS is a clinically useful prediction measure that adjusts prognosis of patients o... more 460 Background: CS is a clinically useful prediction measure that adjusts prognosis of patients on the basis of survival since treatment initiation or therapy duration. CS was recently reported in mRCC patients treated with VEGF targeted therapy in patients stratified by Heng’s criteria. CS has not been reported in mRCC in the context of treatment with HD IL-2. Methods: Patients with histologically confirmed clear cell mRCC treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 were evaluated. Performance status and prognostic risk groups were included. Two-year CS was defined as the probability of surviving an additional 2 years from initiation of HD IL-2 to 18 months after the start of HD IL-2 at 3-month intervals estimated by Kaplan-Meier methodology. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. The median overall survival from HD IL-2 administration was 817 days. St...
Cancers
Background: Non-overlapping somatic mutations in BRAF, NRAS, or NF1 genes occur in 85% of metasta... more Background: Non-overlapping somatic mutations in BRAF, NRAS, or NF1 genes occur in 85% of metastatic melanoma patients. It is not known whether these mutations affect immunotherapy outcome. Materials and methods: Next-Gen sequencing of 324 oncogenes was performed in 73 metastatic melanoma patients. A retrospective review of immunotherapy outcome was performed. Results: BRAF fusions/internal rearrangements, BRAF V600E, NRAS, NF1 mutations, and triple-negative genotypes occurred in 6.9%, 30.1%, 17.8%, 32.9%, and 12.3% of patients, respectively. Median potential follow-up was 41.0 months. Patients with BRAF fusion/rearrangement had decreased progression-free and overall survival (p = 0.015). The other genotypes each had similar progression-free and overall survival. Patients who achieved a complete best objective response at 12 months (n = 36, 49.3%) were found to have significantly improved survival compared those who failed to achieve remissions (n = 37, 50.7%, p < 0.001). Conclus...
Cancers, 2024
Abstract: Previous studies suggested that somatic BRAF and NRAS mutations in metastatic melanoma ... more Abstract: Previous studies suggested that somatic BRAF and NRAS mutations in metastatic melanoma increase the risk for brain metastases. The risk related to other non-overlapping “driver” mutations is unknown. We performed a retrospective evaluation of the incidence, timing, and outcome of brain metastases in a population of melanoma patients that underwent uniform next-gen sequencing. All patients were treated with initial checkpoint inhibitor therapy. Seventeen of 88 patients (20.0%) developed brain metastases. Eleven patients had brain metastases at diagnosis (12.9%). These were all patients with BRAF V600 or NF1 mutations. Only six patients with NRAS, NF1, KIT, or BRAF mutations (including fusions/internal rearrangements experienced delayed CNS progression following immunotherapy (7.1%)). No “quadruple negative” patient developed brain metastases. Patients with brain metastases at diagnosis had a better outcome than those with delayed intracranial progression. Current predictive markers, (LDH, tumor mutation burden, and PDL1) were poorly correlated with the development of brain metastases. Treatment with immunotherapy appears to reduce the incidence of brain metastases. Next-gen molecular sequencing of tumors in metastatic melanoma patients was useful in identifying genetic subpopulations with an increased or reduced risk of brain metastases. This may allow eventual personalization of screening strategies.
Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell ... more Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n ¼ 10) or without (n ¼ 3) prior cryopreservation. Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457-65. Ó2014 AACR.
Cancers, Jan 30, 2024
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Clinical Oncology, Oct 1, 2005
Familial melanoma patients are reported to present with thinner melanomas, to be younger at the t... more Familial melanoma patients are reported to present with thinner melanomas, to be younger at the time of diagnosis, and to have a greater likelihood of developing multiple primary tumors. We sought to determine whether melanomas that occur in a familial setting demonstrate different prognostic and survival statistics relative to sporadic melanoma. Patients and Methods This population-based study used the Utah Cancer Registry and Utah Population Database to objectively evaluate prognostic and survival statistics of the familial melanoma population. From 1973 to 1999, there were 7,785 cases of invasive melanoma identified through the Utah Cancer Registry. These were linked to the Utah Population Database, resulting in 2,659 subjects with family-history information from which a familiality score could be calculated. Cases scored in the top ninth percentile were assigned as high familial risk, and the remaining 91% were considered low familial risk. Results Multivariate logistic-regression analysis found no association between sex, Breslow depth, Clark level, or survival and the familial status. Age at first diagnosis of invasive melanoma was slightly lower in the high-familial-risk group (57 v 60 years; P ϭ .03). High-familial-risk subjects had more melanomas diagnosed at age 30 or younger (12% v 6%; P Ͻ .001). A significant difference in the overall number of individuals with two or more primary malignant melanomas was not detected among the groups (P ϭ .2). Conclusion These data suggest that melanomas occurring in the context of an underlying inherited susceptibility do not have a significantly different biologic behavior.
Haemophilia, Nov 1, 1999
The effects of a recombinant factor IX product (BeneFix), and of five plasma‐derived factor IX pr... more The effects of a recombinant factor IX product (BeneFix), and of five plasma‐derived factor IX products, AlphaNine, Immunine, Konyne, Mononine and Replinine on in vitro peripheral blood mononuclear cell (PBMC) immune function were compared in a blinded study. We assessed the effects of these products on Con‐A‐induced lymphocyte proliferation and interleukin‐2 and interleukin‐10 secretion, expression of lymphocyte activation markers, and nitric oxide secretion by stimulated mouse peritoneal macrophages. At 1 mL–1 for 48 h, Konyne reduced Con‐A‐induced mitogenesis by 50% (P < 0.05); AlphaNine, Mononine and BeneFix had no effect. At 10 IU mL–1, Con‐A‐induced mi‐ togenesis was at control levels with Mononine and BeneFix, but was reduced to <15% (P < 0.05) with each of the other products. IL‐2 and IL‐10 secretion by Con‐A‐stimulated lymphocytes was also markedly depressed by all the products tested except Mononine and BeneFix. Dialysis of these products did not substantially affect these results. Flow cytometric analysis of lymphocyte activation markers following Con‐A stimulation showed that Konyne also decreased IL‐2 receptor α and β chain (CD25 and CD122) induction on PBMC. Konyne also inhibited nitric oxide secretion to levels <18% of controls. These results indicate that certain factor IX products, including some of purported higher purity, substantially depress in vitro immune function. The importance of these findings to in vivo immune function in haemophilia B patients remains to be established.
Journal of The National Comprehensive Cancer Network, Mar 31, 2023
Annals of case reports, Jul 18, 2022
Introduction: Checkpoint inhibitor (CKI) therapy has markedly altered the survival of patients wi... more Introduction: Checkpoint inhibitor (CKI) therapy has markedly altered the survival of patients with many solid tumors. It appears clear that 10-40% of patients with a number of metastatic cancers can achieve lengthy remissions following CKI therapy. The optimal duration of treatment or whether treatment can ever be safely stopped is still controversial. Based on melanoma-derived data, we tested whether CKI treatment could safely be discontinued in patients with other solid tumors. Methods: A retrospective analysis was performed in adults with metastatic solid tumors treated with CKI-based therapy. Patients with solid tumors who achieved complete remission on 2 sequential scans at least 3 months apart during ongoing treatment were identified from our computerized patient database. Patient data was analyzed for patient characteristics, as well as progression-free and overall survival. Results: A total of 69 non-melanoma solid tumor patients were treated with CKI-based regimens in our clinic and 14 achieved complete remission (20.3%). Five patients were female (35.7%) and the remaining nine were male (64.3%). A 100% progressionfree survival was observed for these patients. The median duration of complete remission was over 20 months from the time of elective treatment discontinuation. Median overall survival was not reached in this cohort. One patient died of non cancerrelated causes. Conclusions: Based on this retrospective case series, elective treatment discontinuation in patients who achieved complete remission appears feasible. All patients remained in a durable complete remission after treatment discontinuation. We hypothesize that appropriate selection of patients for early treatment discontinuation may decrease their economic burden related to ongoing treatment, limit potential toxicity, and improve quality of life.
Research Square (Research Square), Apr 5, 2021
Background: Virtually all metastatic melanoma patients who progress after initial treatment with ... more Background: Virtually all metastatic melanoma patients who progress after initial treatment with PD-1 or CTLA-4 directed antibodies will die of their disease. Salvage options are urgently needed. It is theoretically attractive to combine immunotherapy with targeted agents in progressing patients with BRAF mutation positive melanoma, but the toxicity of combined treatment has proven challenging. We have observed striking responses with the cautious addition of low doses of targeted therapy to PD-1 antibody treatment at the time of disease progression following initial immunotherapy. This allowed conversion of a signi cant number of rapidly progressing patients to durable complete responses in BRAF mutant melanoma. Results: We therefore performed a retrospective analysis of our large patient database and identi ed 23 patients who progressed on initial checkpoint inhibitor treatment, who subsequently had cautious addition of BRAF±MEK inhibitor therapy to PD-1 antibody treatment. We found an objective response rate of 55% in second line therapy, with a median progression-free survival of 33.4 months and median overall survival of 34.1 months, with 40% of patients in remission over 3 years. Ten of 12 responding patients were able to discontinue all therapy and continue in unmaintained remission. Toxicity of this approach was generally manageable (only 21.7 % grade 3-5 toxicity). There was 1 early sudden death for unknown reasons in a responding patient. Conclusions: Our results suggest that 2 nd line therapy with PD-1 inhibitors plus BRAF±MEK inhibitors has substantial activity and manageable toxicity. This treatment can induce additional durable complete responses after failure of initial immunotherapy of metastatic melanoma. These remarkable results suggest further evaluation be performed of sequential checkpoint inhibitor therapy with cautious addition of targeted therapy in appropriate patients.
Drs. Rini and Bukowski do an excellent job of updating and commenting on the rapidly evolving fie... more Drs. Rini and Bukowski do an excellent job of updating and commenting on the rapidly evolving field of therapy for metastatic renal cell carcinoma (RCC).
Modecular medicine and medicinal, Oct 1, 2010
American Journal of Roentgenology, Oct 1, 1997
H igh-dose interleukin-2 (IL-2)-based treatment induces objective regressions in l3 35% of patien... more H igh-dose interleukin-2 (IL-2)-based treatment induces objective regressions in l3 35% of patients with metastatic or unresectable renal cell carcinoma, with 3-I 1% complete responses [1]. In many other patients. IL-2 immunotherapy induces prolonged disease stabilization. Thus, on radiography. residual abnormalities after treatment may represent viable, but quiescent, tumor that will eventually progress. Alternatively, studies such as chest radiography, CT. and MR imaging may underestimate treatment responses. Furthermore,
Frontiers in oncology, Mar 14, 2024
Mucosal melanoma represents an uncommon melanoma subtype. Wide excision has long represented the ... more Mucosal melanoma represents an uncommon melanoma subtype. Wide excision has long represented the standard therapeutic approach. Unfortunately, there is a high relapse rate and mortality. Neoadjuvant therapy with ipilimumab plus nivolumab has shown significant activity in cutaneous melanoma. We present two cases of mucosal melanoma, each with potential regional dissemination, who were treated with neoadjuvant immunotherapy with minimal toxicity. Both patients were closely monitored and achieved radiologic and pathologic complete responses. These patients were able to avoid radical surgery and related functional consequences. Both patients remain recurrence-free with protracted follow-up. The potential usefulness of neoadjuvant immunotherapy as an organ preservation strategy in mucosal melanoma deserves further evaluation in prospective clinical trials.
The Journal of Clinical Endocrinology & Metabolism, 1997
Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatmen... more Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatment, patients develop severe hypocholesterolemia along with striking alterations in the concentration and composition of the circulating lipoproteins. The present study was undertaken to gather information about the pathogenesis of these abnormalities. Patients were studied before-, during-and after a 5-day course of high dose iv rIL-2. Whole plasma cholesterol was markedly reduced by rIL-2 administration (52%; P Ͻ 0.001), whereas the triglyceride concentration did not change. Thus, the lipoproteins became triglyceride enriched (P ϭ 0.004). Low density lipoprotein cholesterol, apolipoprotein B (apoB), high density lipoprotein cholesterol, and apoA-I concentrations all decreased. Esterified cholesterol levels were markedly reduced. Total plasma apoE increased markedly, and two kinds of abnormal particles appeared: 1) -migrating, very low density lipoproteins; and 2) discoidal, apoE-and phospholipid-containing particles with abnormal density and electrophoretic mobility. The activities of two lipoprotein triglyceride hydrolases, lipoprotein lipase and hepatic lipase, fell significantly during treatment and returned promptly to pretreatment levels after rIL-2 was discontinued. Lecithin:cholesteryl acyltransferase (LCAT) activity also decreased significantly (64%) during treatment, but in contrast to the lipases, remained low for at least 5 days after the last dose of rIL-2 (P Ͻ 0.001). High dose iv rIL-2 induces severe dyslipidemia with deficiencies of both postheparin lipases and acute LCAT deficiency. Most, if not all, of the lipoprotein changes observed are explained by the LCAT deficiency that follows IL-2-induced hepatocellular injury and cholestasis.
Journal of Clinical Oncology, May 20, 2015
4565 Background: The aim of this study is to determine if achievement of stable disease as a best... more 4565 Background: The aim of this study is to determine if achievement of stable disease as a best response to HD IL-2 may improve survival outcomes. Recent data suggest that immunotherapy may improve survival even in those pts who do not experience objective responses (CR+PR). Methods: All sequential mRCC pts treated with HD IL-2 at the University of Utah (1988-2013) and University of Michigan (1997-2013) were included. Best responses to HD IL-2 were correlated with survival outcomes using landmark analysis at 2 months—the median time to first disease assessment. Results: A total of 391 pts (75% male; median age 55 yrs, range 13-77) were included and belonged to the following risk categories: 80 (20%) good, 251 (64%) intermediate, and 60 (15%) poor. A CR was identified in 35 (9%), PR in 39 (10%), SD in 125 (32%), progressive disease (PD) in 164 (42%), and not evaluable for response (NE) in 28 (7%) pts. Median OS for the favorable, intermediate and poor risk groups were 53.8 (p=0.0015 vs intermediate), 26....
Cancer Research, Apr 1, 2004
658 Selective expression of cytokines on the surface of tumors is likely to stimulate tumor-infil... more 658 Selective expression of cytokines on the surface of tumors is likely to stimulate tumor-infiltrating lymphocytes that are primed and already recognize tumor antigens. This may result in enhanced tumor recognition and killing. This gene therapy approach may avoid toxicity associated with systemic therapy with high doses of the cytokines needed to achieve the same effects. In order to test this concept, we have evaluated an IL-2 gene construct that is designed to induce tumor cells to express a membrane bound form of IL-2 (IL-2tm). A mammalian plasmid expression vector was designed to express a fusion gene consisting of human interleukin 2 with a Fc receptor epsilon transmembrane anchor derived from the gamma subunit of the Fc receptor epsilon. We demonstrated that mRNA and protein for the IL-2tm fusion protein was expressed in transfected RD995 tumor cells. Expression of the IL-2tm protein on the tumor cell surface membrane was confirmed by laser confocal microscopy. In order to assess biological function, RD995 transfected with IL-2tm or the empty expression vector (pCMV2b) were implanted subcutaneously into C3H/HEN mice. Non-transfected RD995 was also implanted subcutaneously for tumor growth comparison (control group). Groups of mice implanted with 10 6 or 10 5 RD995 transfected with IL-2tm grew considerably more slowly than RD995 transfected with pCMV2b or non-transfected control RD995 implanted tumors. Further preclinical evaluation of the IL-2tm gene therapy as a possible cancer treatment is underway.
Journal of Clinical Oncology, 2012
10614 Background: Identification of rare (>2-5) circulating tumor cells (CTC) in 7.5 ml blood ... more 10614 Background: Identification of rare (>2-5) circulating tumor cells (CTC) in 7.5 ml blood by immunofluorescence assay (IFA) correlates with a poor prognosis in colon, breast, prostate and lung cancer. Changes in CTC count during treatment also predict the eventual patient progression and survival in these cancers. Existing assays do not detect melanoma CTC, however. In addition, isolation of viable CTC remains problematic. To overcome these limitations we attempted to develop novel melanoma CTC assays, using IFA and cell culture approaches. Methods: Blood samples were obtained from patients and controls following informed consent. The buffy coat (white cells + tumor) was isolated by Ficoll/Hypaque centrifugation, and split into 6 replicate cultures in proprietary TrueCells medium. After 21 days in culture, tumor colonies were counted, and stained for melanoma and leukocyte markers. Buffy coat cells from parallel blood samples were stained with a panel of CSPG4-specific mAb (a...
Journal of Clinical Oncology, 2014
487 Background: HD IL-2 is associated with an objective response rate of 16-20% with durability o... more 487 Background: HD IL-2 is associated with an objective response rate of 16-20% with durability of response in select mRCC patients. HD IL-2 is also associated with significant toxicity including vascular leak syndrome and inflammatory side effects. Few predictive markers can identify patients likely to respond to HD IL-2. Methods: Patients treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 with clear cell mRCC were evaluated. Grade of toxicities during HD IL-2 treatment were collected based on provider documentation in the electronic health record. Rates of adverse events (AEs) and overall survival stratified grade 3 AEs were evaluated by Kaplan-Meier survival estimates and Cox proportional hazards models. All AEs were graded per common terminology criteria version 4. Grade 3 rigors were defined as severe rigors requiring opioids. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) ...
Journal of Clinical Oncology, 2014
460 Background: CS is a clinically useful prediction measure that adjusts prognosis of patients o... more 460 Background: CS is a clinically useful prediction measure that adjusts prognosis of patients on the basis of survival since treatment initiation or therapy duration. CS was recently reported in mRCC patients treated with VEGF targeted therapy in patients stratified by Heng’s criteria. CS has not been reported in mRCC in the context of treatment with HD IL-2. Methods: Patients with histologically confirmed clear cell mRCC treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 were evaluated. Performance status and prognostic risk groups were included. Two-year CS was defined as the probability of surviving an additional 2 years from initiation of HD IL-2 to 18 months after the start of HD IL-2 at 3-month intervals estimated by Kaplan-Meier methodology. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. The median overall survival from HD IL-2 administration was 817 days. St...
Cancers
Background: Non-overlapping somatic mutations in BRAF, NRAS, or NF1 genes occur in 85% of metasta... more Background: Non-overlapping somatic mutations in BRAF, NRAS, or NF1 genes occur in 85% of metastatic melanoma patients. It is not known whether these mutations affect immunotherapy outcome. Materials and methods: Next-Gen sequencing of 324 oncogenes was performed in 73 metastatic melanoma patients. A retrospective review of immunotherapy outcome was performed. Results: BRAF fusions/internal rearrangements, BRAF V600E, NRAS, NF1 mutations, and triple-negative genotypes occurred in 6.9%, 30.1%, 17.8%, 32.9%, and 12.3% of patients, respectively. Median potential follow-up was 41.0 months. Patients with BRAF fusion/rearrangement had decreased progression-free and overall survival (p = 0.015). The other genotypes each had similar progression-free and overall survival. Patients who achieved a complete best objective response at 12 months (n = 36, 49.3%) were found to have significantly improved survival compared those who failed to achieve remissions (n = 37, 50.7%, p < 0.001). Conclus...
Cancers, 2024
Abstract: Previous studies suggested that somatic BRAF and NRAS mutations in metastatic melanoma ... more Abstract: Previous studies suggested that somatic BRAF and NRAS mutations in metastatic melanoma increase the risk for brain metastases. The risk related to other non-overlapping “driver” mutations is unknown. We performed a retrospective evaluation of the incidence, timing, and outcome of brain metastases in a population of melanoma patients that underwent uniform next-gen sequencing. All patients were treated with initial checkpoint inhibitor therapy. Seventeen of 88 patients (20.0%) developed brain metastases. Eleven patients had brain metastases at diagnosis (12.9%). These were all patients with BRAF V600 or NF1 mutations. Only six patients with NRAS, NF1, KIT, or BRAF mutations (including fusions/internal rearrangements experienced delayed CNS progression following immunotherapy (7.1%)). No “quadruple negative” patient developed brain metastases. Patients with brain metastases at diagnosis had a better outcome than those with delayed intracranial progression. Current predictive markers, (LDH, tumor mutation burden, and PDL1) were poorly correlated with the development of brain metastases. Treatment with immunotherapy appears to reduce the incidence of brain metastases. Next-gen molecular sequencing of tumors in metastatic melanoma patients was useful in identifying genetic subpopulations with an increased or reduced risk of brain metastases. This may allow eventual personalization of screening strategies.