Abstract
Interview by Jenaid Rees, Commissioning Editor
Jeffrey S Weber, MD, PhD, is the current Director of the Donald A Adam Comprehensive Melanoma Research Center of Excellence and is a senior member at the Moffitt Cancer Center (Tampa, FL, USA). After achieving his PhD in molecular cell biology from Rockefeller University (NY, USA) and then a medical degree from New York University Medical Center (NY, USA), Dr Weber went on to complete a residency in internal medicine for the University of California, San Diego (CA, USA) before undertaking his fellowships at the National Cancer Institute (MD, USA). His main clinical interest involves immunotherapy for melanoma and other malignancies, and he has been working in the field of melanoma therapeutics for over 20 years. In this time, he has published more than 120 articles in peer reviewed journals and has served on several scientific boards including the Melanoma Research Foundation Scientific Advisory Committee and the scientific advisory board of the Melanoma Therapeutics Foundation. He has been peer review funded continuously by the NIH for over 18 years and has held over a dozen investigational new drug applications with the US FDA.
What led you to specialize in the field of tumor immunology & melanoma?
My postdoctoral experience after my medical oncology fellowship was in Steven Rosenberg’s laboratory at the NIH in Bethesda (MD, USA) during a time in the mid-1980s when there was an explosion of information and new knowledge in tumor immunology and the first real hope that the immune system could be harnessed to benefit patients with cancer, particularly melanoma. It was this inspiring experience under the supervision of Rosenberg and the tutelage of James Mulé at NIH that led me into the field of melanoma and tumor immunology.
I understand you focus on novel translational clinical trials in melanoma, what research are you currently working on?
In our Comprehensive Melanoma Research Center at the Moffitt Cancer Center (FL, USA), we focus on: new combinations of checkpoint protein inhibitor trials with PD-1 antibodies; combinations of either targeted or immune therapies with adoptive cell therapy using tumor-infiltrating lymphocytes; new combinations to augment the clinical effectiveness of the CTLA4-blocking antibody, ipilimumab, and combinations of BRAF inhibitors with Hsp90 or PI3K inhibitors to overcome resistance to BRAF drugs. All of these trials are based on basic scientific work done in our own laboratories at the Moffitt Cancer Center.
You recently identified a unique melanoma gene signature with the potential to diagnose patients suitable for immunotherapy. How do you envisage this impacting on melanoma management?
At the Moffitt Cancer Center, Mulé has spearheaded the work with tumor-immune gene signatures as noted earlier and we will prospectively test the idea that this signature has predictive value in upcoming combination trials of checkpoint protein inhibition with PD-1- and CTLA4-blocking antibodies Citation[1]. This signature comprises a rapid and easily performed test that could help us choose appropriate candidates for immunotherapy.
Medscape recently reported ‘Unprecedented Advances in Melanoma’ to be the top game changer in the field of oncology in 2011 due to the efficacy of ipilimumab & vemurafenib. In the light of your recent work highlighting the adverse events of ipilimumab, would you agree with this view?
The novel immune-related side effects of ipilimumab do not detract from the clear benefits the drug induces in patients with melanoma Citation[2]. Those side effects, which are dose limiting approximately 10% of the time at the FDA-approved dose of 3 mg/kg, can be easily managed. Although they require a bit of a learning curve to master, they are no more complex to manage than any chemotherapy-related side effects that I have dealt with as an oncologist Citation[3]. Therefore, I would certainly agree that in spite of its known immune-related side effects, the development of ipilimumab is indeed a game changer.
What do you feel has been your greatest achievement to date?
Being able to work together with an outstanding group of scientists, clinicians and epidemiologists at the Moffitt Cancer Center to assemble a SPORE application in cutaneous malignancies for submission to the National Cancer Institute. In my own work, promoting the use of checkpoint protein antibodies such as ipilimumab and BMS 936558 for the treatment of metastatic and resected melanoma and understanding whether patients might benefit from their use is what I am most proud of.
What do you think are the key areas of development in the field of melanoma diagnosis & prognosis?
The sequencing of the melanoma genome and the elucidation of the melanoma kinome will have huge effects on the development of new treatments and on the creation of new ways to monitor the growth of disease and the likelihood of patients becoming resistant to targeted and immune therapies. There will also be major advances in the use of biomarkers to predict sensitivity to immune treatments. Adoptive cell therapy will reach maturity, and new combinations of immune-checkpoint protein inhibitors and/or targeted therapies with adoptive cell therapies will enter mainstream treatment.
What recent studies have been of particular interest to you & why?
The fact that patients can be treated with a second checkpoint protein inhibitor such as PD-1 antibody and still derive significant clinical benefit after failing CTLA4 blockade with ipilimumab and vice versa, is one of the most clinically interesting and important recent advances in the immunotherapy field, suggesting that combination or sequential studies of those antibodies should be undertaken. In addition, the possibility of combining targeted and immune therapy, such as the trial headed by Amod Sarnaik that we have recently started, here at the Moffitt Cancer Center, of ipilimumab with tumor-infiltrating lymphocytes, is of great interest and importance for the field of immunotherapy.
You are the director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence (FL, USA), what do you feel has been the Center’s most important achievement to date & what do you hope to achieve in this role?
The most important achievements of the Center, of which there have been many, have been to translate laboratory advances in BRAF resistance from Keiran Smalley (Moffitt Cancer Center) to a trial, led by Vernon Sondak and Ragini Kudchadkar at the Center, of vemurafenib plus the HSp90 inhibitor, XL888; the translation of work from Mulé and Shari Pilon Thomas at the Center to a clinical trial of adoptive cell therapy combined with targeted and/or immune therapy led by Sarnaik; the complete and targeted sequencing of over 100 melanomas that I have spearheaded with our colleagues Li Ding and Rick Wilson at The Genome Institute, Washington University in St Louis (MO, USA), the work referred to previously by Mulé and Jane Messina, the work by Eduardo Sotomayor and colleagues at the Center that support a role for HDAc inhibitors as immune modulators in melanoma, the work from Dmitry Gabrilovich at the Center suggesting that targeted and immune therapies have a major role in combination and finally the work by Dana Rollison and Anna Giuliano at the Center indicating that there is a role for human papillomaviruses in the etiology of squamous skin cancer. All of these advances have the potential to make a major impact on cutaneous malignancies in the near future.
Where do you think the field of melanoma diagnosis & management will be in the next 10 years?
In the future, I think every patient with melanoma at the time of diagnosis will undergo a comprehensive blood test assessing their melanoma genome using circulating tumor DNA. This baseline assay, plus subsequent measurements, will determine treatment pathways or whether treatment is needed in the first instance. This will be an iterative process with constant monitoring to make decisions on what treatments are indicated. Similarly, both tumor assays and peripheral blood assays at baseline and over time will determine the immune treatments that will complement targeted treatments. Adjuvant treatments will be increasingly successful and will significantly decrease the likelihood of ever developing unresectable metastatic disease. For those with metastatic disease, melanoma, like many cancers in the future, will become a chronic disease akin to HIV managed with HAART today.
Financial & competing interests disclosure
JS Weber has been supported by honoraria of less than US$10,000 yearly from GlaxoSmithKline, BMS, Genentech and Roche. The Moffitt Cancer Center, but not JS Weber personally, receives clinical research funding from GlaxoSmithKline, BMS, Genentech and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Messina JL, Fenstermacher DA, Eschrich S et al. 12-chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci. Rep. 2, 765 (2012).
- Cheson BD, Kerr DJ, Kris MG et al. 2011 top game changers in oncology. Medscape 23 November 2011.
- Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30(21), 2691–2697 (2012).