Donald am Comprehensive Melanoma Research Center

Sun City Center, FL, United States

Donald am Comprehensive Melanoma Research Center

Sun City Center, FL, United States
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Freeman-Keller M.,University of South Florida | Kim Y.,H. Lee Moffitt Cancer Center and Research Institute | Cronin H.,H. Lee Moffitt Cancer Center and Research Institute | Richards A.,H. Lee Moffitt Cancer Center and Research Institute | And 2 more authors.
Clinical Cancer Research | Year: 2016

Purpose: Retrospective analysis of irAEs in melanoma patients treated with nivolumab. Experimental Design: Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs. Results: IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P = 0.001), and OS benefit was noted in patients who reported three or more irAE events (P= 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243-0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036-0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis). Conclusions: Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses. © 2016 American Association for Cancer Research.


PubMed | Donald am Comprehensive Melanoma Research Center, Moffitt Cancer Center, University of South Florida and Lombardi Comprehensive Cancer Center
Type: Clinical Trial, Phase I | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Retrospective analysis of irAEs in melanoma patients treated with nivolumab.Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs.IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P 0.001), and OS benefit was noted in patients who reported three or more irAE events (P 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243-0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036-0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis).Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses.


Chacon J.A.,University of Pennsylvania | Sarnaik A.A.,Donald am Comprehensive Melanoma Research Center | Pilon-Thomas S.,Donald am Comprehensive Melanoma Research Center | Radvanyi L.,H. Lee Moffitt Cancer Center and Research Institute | Radvanyi L.,Lion Biotechnologies
OncoImmunology | Year: 2015

TIL from solid tumors can express activation/co-stimulatory molecules like 4–1BB/CD137, a sign of recent antigenic stimulation in the tumor microenvironment (TME). This activated state can be exploited ex vivo to enhance the expansion of tumor-reactive CD8+ TIL for adoptive cell therapy through direct addition of immunomodulators to tumor fragments in culture. © 2015, Taylor & Francis Group, LLC.


Dubinett S.M.,University of California at Los Angeles | Lee J.M.,University of California at Los Angeles | Sharma S.,University of California at Los Angeles | Mule J.J.,Donald am Comprehensive Melanoma Research Center
Cancer Journal | Year: 2010

Chemokines (ie, chemoattractant cytokines) are a family of small secreted molecules that mediate leukocyte migration. It is becoming increasingly more evident that chemokines play an integral role in the initiation of a specific immune response. With respect to cancer, chemokines are being studied for both their role in tumor biology and as promising immunotherapy candidates. We review several areas of chemokine importance in tumor immunity and discuss the experimental evidence that is leading to the clinical use of this cytokine family in new treatment approaches for patients with cancer. Copyright © Lippincott Williams & Wilkins.


Wolchok J.D.,Sloan Kettering Cancer Center | Yang A.S.,Sloan Kettering Cancer Center | Weber J.S.,Donald am Comprehensive Melanoma Research Center
Cancer Journal | Year: 2010

During the past decade, new insights into the mechanisms by which T-cell activation and proliferation are regulated have led to the identification of checkpoint proteins that either up-or down-modulate T-cell reactivity. In the presence of active malignancy, pathophysiologic inhibition of T-cell activity may predominate over stimulation. A number of antibodies have been generated that can block inhibitory checkpoint proteins or promote the activity of activating molecules. In murine models, their use alone or with a vaccine strategy has resulted in regression of poorly immunogenic tumors and cures of established tumors. The prototypical immune regulatory antibodies are those directed against cytotoxic T-lymphocyte antigen-4, a molecule present on activated T cells. In this review, the preclinical rationale and clinical experience with 2 anticytotoxic T-lymphocyte antigen-4 antibodies are extensively discussed, demonstrating that abrogation of an immune inhibitory molecule can result in significant regression of tumors and longlasting responses. The unique kinetics of antitumor response and the characteristic immune-related side effects of ipilimumab are also discussed. This clinical efficacy of this promising antitumor agent has been evaluated in 2 randomized phase III trials, whose results are eagerly awaited. Programmed death (PD)-1 is another immune inhibitory molecule against which an abrogating human antibody has been prepared. Initial preclinical testing with anti-PD-1 and anti-PD-L1 has shown encouraging results. Stimulatory molecules such as CD40, 41-BB, and OX-40 are also targets for antibody binding and activation, not blockade, and early dose ranging trials with antibodies against all 3 have shown that they can mediate regression of tumors, albeit with their own spectrum of side effects that are different from those that occur with abrogation of immune inhibition. Copyright © Lippincott Williams & Wilkins.


Hernandez-Chacon J.A.,University of Texas M. D. Anderson Cancer Center | Li Y.,University of Texas M. D. Anderson Cancer Center | Wu R.C.,University of Texas M. D. Anderson Cancer Center | Bernatchez C.,University of Texas M. D. Anderson Cancer Center | And 4 more authors.
Journal of Immunotherapy | Year: 2011

Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose interleukin-2 is a promising form of immunotherapy for stage IV melanoma having clinical response rates of 50% or more. One of the major problems preventing further success of this therapy is that the current protocols used to highly expand TIL for infusion drive CD8 T cells to differentiate into effector cells losing key costimulatory molecules such as CD28 and CD27. This has been associated with a lack of persistence in vivo for reasons not entirely clear. In this study, we demonstrate that while human melanoma CD8 TIL lost CD27 and CD28 expression during the rapid expansion for ACT, they gained expression of the alternative costimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Postrapid expansion protocol (REP) TIL were found to be highly sensitive to activation-induced cell death when reactivated through the T-cell receptor with low levels of OKT3 antibody. However, coligation of 4-1BB using 2 different agonistic anti-4-1BB antibodies potently prevented activation-induced cell death of post-REP CD8 TIL, including those specific for melanoma antigen recognized by T cells, and facilitated even further cell expansion. This was correlated with increased levels of bcl-2 and bcl-xL together with decreased bim expression. 4-1BB costimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced cytotoxic T-cell activity against melanoma cells. Lastly, post-REP CD8 TIL were protected from cell death by anti-4-1BB ligation when exposed to human leukocyte antigen-matched melanoma cells. Our results indicate that 4-1BB costimulation may significantly improve TIL survival during melanoma ACT and boost antitumor cytolytic activity. © 2011 by Lippincott Williams & Wilkins.


Ding L.,Washington University in St. Louis | Kim M.,Donald am Comprehensive Melanoma Research Center | Kanchi K.L.,Washington University in St. Louis | Dees N.D.,Washington University in St. Louis | And 17 more authors.
PLoS ONE | Year: 2014

To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3′ base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma. © 2014 Ding et al.


Baksh K.,Donald am Comprehensive Melanoma Research Center | Baksh K.,University of South Florida | Weber J.,Donald am Comprehensive Melanoma Research Center
Seminars in Oncology | Year: 2015

Over the last two decades, our understanding of the molecular basis of immunity has revealed the complexity of regulatory pathways involved in immune responses to cancer. A significant body of data support the critical importance of immune checkpoints in the control of the adaptive immune response to malignancy, and suggest that inhibitors of those checkpoints might have significant utility in treating cancer. This has been borne out by the recent US Food and Drug Administration (FDA) approvals of two different antibodies, one against cytotoxic T-lymphocyte antigen-4 (CTLA-4) and one against programmed death-1 (PD-1). Here, we provide a comprehensive review of the literature regarding the preclinical justification for the use of CTLA-4 and PD-1 blockade as monotherapy, and as combination therapy in the treatment of cancer. The animal data strongly supported the use of these drugs in patients, and in many cases suggested strategies that directly led to successful registration trials. In contrast, many of the toxicities, and some of the unusual response patterns seen in patients with these drugs, were not predicted by the preclinical work that we cite, highlighting the importance of early-phase trials with patients to inform future drug development. In addition, we review herein the preclinical data surrounding emerging immune checkpoint proteins, including BTLA, VISTA, CD160, LAG3, TIM3, and CD244 as potential targets for inhibition. The current comprehensive review of the literature regarding CTLA-4 and PD-1, as well as a number of novel checkpoint proteins demonstrates a strong preclinical basis for the use of these antibodies singly and in combination to overcome checkpoint inhibition in the treatment of cancer. We also suggest that the use of these antibodies may augment the efficacy of other activating immune antibodies, cytokines, radiation, and adoptive cell therapy in human cancer. © 2015 Elsevier Inc.


Chacon J.A.,University of Texas M. D. Anderson Cancer Center | Wu R.C.,University of Texas M. D. Anderson Cancer Center | Sukhumalchandra P.,University of Texas M. D. Anderson Cancer Center | Molldrem J.J.,University of Texas M. D. Anderson Cancer Center | And 5 more authors.
PLoS ONE | Year: 2013

Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the "rapid expansion protocol" (REP) were not designed to enhance the generation of optimal effector-memory CD8+ T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8+ effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8+ T cells, on the yield, phenotype, and functional activity of expanded CD8+ T cells during the REP. We found that CD8+ TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8+ T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8+ post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8+ T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients. © 2013 Chacon et al.


PubMed | Washington University in St. Louis and Donald am Comprehensive Melanoma Research Center
Type: Journal Article | Journal: PloS one | Year: 2014

To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3 base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.

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