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'Clinical Trials Remain Essential to Evaluate Combination Immunotherapies, and Against a Broader Range of Cancers' (11/10/13 issue)

I am writing to salute Dr. Jedd Wolchok for his inspirational "Voices" column in the November 10 issue, and echo his call for more clinical trials to evaluate combination immunotherapies.


As he points out, the rapid and durable responses observed in patients with melanoma and kidney cancers suggest a potential role for combination immunotherapy in treating other types of cancer, and I applaud efforts to pursue this approach more broadly. Numerous research initiatives are investigating the purported synergistic effects of combining immunotherapeutic agents with molecularly targeted therapies, PD-1 antibodies, or other checkpoint inhibitors as a means to improve outcomes and potentially individualize anticancer treatment. Other investigations are evaluating whether sequential treatment with two complementary immunotherapies may yield improvements in clinical endpoints over those seen with single-agent immunotherapy, while preserving other downstream treatment options.


While other cancer types appear to be fertile ground for investigating combination immunotherapy, much remains to be learned about this approach in advanced melanoma and kidney cancer. That is the rationale for the PROCLIVITY clinical trial program, which is investigating the use of high-dose interleukin-2 (HD IL-2) in combination with various inhibitors of BRAF, CTLA4, and tyrosine kinase in patients with metastatic melanoma or metastatic renal cell carcinoma. The PROCLIVITY investigators aim to assess whether HD IL-2-based combination therapy provides a more robust and durable response, compared with HD IL-2 monotherapy, and to identify the optimal sequencing of individual agents in combination regimens.


Findings from these and other trials may help refine the administration of combination immunotherapy as a means to improve treatment outcomes across various cancer types. To paraphrase Dr. Wolchok and his patient, Mary Elizabeth Williams [as noted, writing in Salon]: we can and should be making these malignancies more treatable for all cancer patients.


Joseph I. Clark, MD, FACP


Professor of Medicine


Loyola University Stritch School of Medicine


Maywood, Ill.


AACR Cancer Progress Report

I reviewed with great interest the recent article on the AACR's 2013 Cancer Progress Report highlighting advances in immunotherapy (OT, 10/25/13 issue). As a clinician who closely follows this area of research, I share the AACR's concern about the current oncology research funding crisis, and echo AACR's call for greater patient participation in cancer clinical trials. Such participation is crucial to the continued advancement and adoption of immunotherapy, a treatment modality that has been shown to produce meaningful and durable responses in a subset of patients, and which is "beginning to revolutionize the treatment of certain cancers," in the words of AACR President Charles L. Sawyers, MD.


Whereas immunotherapeutic agents such as ipilimumab and interleukin-2 (IL-2) are thought to modulate "natural immunity," the nature of their clinical effector process is not well understood. When we have therapies capable of durable response but such benefits are limited to a select group of patients, greater effort needs to be applied to identifying the predictive and prognostic markers of response. Understanding such biomarkers will enhance response rates (i.e., by enabling selection of appropriate patients) and limit toxicity (i.e., by facilitating appropriate dosing). In addition, biomarker studies tied to clinical trials will provide a basis for rational combinations.


Registration databases have been established for ipilimumab and IL-2, and clinical trials such as the ongoing PROCLIVITY program are advancing understanding of combination immunotherapy. However, the lack of significant funding outside of industry has limited understanding of biomarkers. While the registration databases are collecting valuable clinical information, they lack annotated tissue samples needed for biomarker studies. Ideally, every patient undergoing immunotherapy should receive immunologic assessments just as they have CT scans and other blood tests. Yet we lack the basic understanding that would allow immunologic assessments. Consequently, we are administering costly therapies to patients who may only experience toxicity.


Policymakers should increase support for translational research focused on understanding the expanding number of tools available to the treating clinician. One such tool is the immune score, a proposed classification system that quantifies the density and location of immune cells within a tumor, and which purportedly has a prognostic value exceeding that of the AJCC/UICC TNM-classification.1 The immune score is emblematic of the huge strides we have made in translational research, and may eventually be regarded as the immunotherapeutic equivalent of molecular targeting, which has led the way to personalized cancer care. Indeed, enhanced understanding of these potentially valuable tools may someday lead us to the era of personalized immunotherapy.


Gregory A. Daniels, MD, PhD


Moores UCSD Cancer Center


La Jolla, Calif.



1. Galon J, Pages F, Marincola FM, et al. The immune score as a new possible approach for the classification of cancer. J Transl Med. 2012;10:1:[Context Link]


Prophylactic Cranial Irradiation & Hippocampus-Sparing Radiotherapy (11/25/13 issue)

Two articles caught my attention in the Nov. 25 issue-one about evidence that whole brain irradiation can be eliminated in patients with CNS lymphoma (; and the other that hippocampus-sparing radiotherapy supports preservation of memory ( The latter article contains the word PCI-i.e., prophylactic cranial irradiation.


Briefly, prophylactic cranial irradiation was introduced several decades ago to reduce the risk of metastatic disease in the brain in patients with limited small-cell lung cancer, whose cancer is in complete remission after treatment with chemotherapy and thoracic irradiation. Meta-analysis of trials have shown that prophylactic cranial irradiation can improve overall survival at three years from 15 percent to 18 percent and 15 percent to 20 percent.1,2 However, because this prophylaxis is associated with substantial side effects and impact on quality of life, the question arises whether the benefits outweigh the risks. The prophylaxis, though, has for years been offered to patients with limited small-cell lung cancer.


Regarding hippocampus sparing, though: Although it may help preserve memory, the result is not absolute and does not prevent other side effects of prophylactic cranial irradiation.


High response rates have been reported in patients with small-cell lung cancer with various systemic therapies.3 It was encouraging to read in the OT article that chemo-immune therapy can replace whole brain irradiation in CNS lymphoma.


Prophylactic cranial irradiation was brought to my attention in the middle of last year and, reviewing treatment for limited small cell lung cancer, it is noteworthy that little has changed in the past 20 years. Moreover, the question arises whether patients always receive an informed consent at the time of discussion of this prophylaxis. Among survivors are patients who declined the prophylaxis and who were treated with effective local control at diagnosis of brain metastatic disease.


In changes to therapy, it is crucial to ascertain that systemic upfront therapy is adequate.


Marlies Van Hoef, MD, PhD, MBA


We welcome comments, suggestions, or other feedback about any of the articles in this or other issues-or on or in our iPad issues. Email; or post on our Facebook page ( OncologyTimesNews).




1. Arriagada et al: Annals of Oncology 2002;13:748-754. [Context Link]


2. Auperin et al: NEJM 1999;341:476-484. [Context Link]


3. Crivellari et al: The Oncologist 2007;12:79-89. [Context Link]