The past 3 years have witnessed transformative changes in the way that solid tumors and hematologic malignancies are approached, in almost every instance now including consideration of some form of immunomodulation in the first- or later-line therapeutic setting. The greatest success has occurred with the advent of immune checkpoint–blocking antibodies, starting with anti–CTLA-4 (cytotoxic T-lymphocyte–associated antigen), which has a relatively low patient benefit rate (about 20% long-term disease control in advanced melanoma) and causes dangerous immune-related toxicities in 10% to 15% of patients.
Blockade of the programmed death (PD)-1/PD ligand-1 (PD-L1) axis between effector T cells and tumor or other cells in the tumor microenvironment has been very promising in single-agent studies in many malignancies, with combination approaches now being investigated. In melanoma, a lower rate of toxicity and a higher clinical benefit rate have been shown with PD-1 blockade in comparison with cytotoxic therapy, as in the report by Weber et al1 summarized in this issue of The ASCO Post, and ipilimumab (Yervoy), as recently reported by Robert et al.2 Although other new immunotherapies such as unmodified antibodies, immunotoxins, bispecific antibodies, and lesional injection of various immunomodulators have also shown activity—and in some cases have already gained regulatory approval—they are beyond the scope of this commentary but may find an important role in combinations or sequences with immune checkpoint blockade.
PD-1/PD-L1 Blockade vs Cytotoxic Chemotherapy
Has PD-1 blockade become the new and nontoxic broad-spectrum anticancer agent, supplanting target-nonspecific cytotoxics like cyclophosphamide, fluorouracil, anthracyclines, taxanes, and platinum agents? The answer is probably yes and no—but what is clear is that these agents are still failing to benefit most patients with malignancy and may still cause unpredictable and dangerous immune-mediated toxicities.
Although such toxicities may be outweighed by the clinical benefit among patients with advanced and sometimes treatment-refractory malignancies, the inevitable exploration of immune checkpoint–blocking antibodies in the adjuvant setting may lead to less favorable therapeutic ratios.3 This could occur if the adjuvant therapy is given to large numbers of patients unselected for the yet-to-be defined predictive factors for benefit, or it could be a result of a requirement for an established tumor microenvironment that has been postulated to be critical for the therapeutic action of PD-1/PD-L1 blockade.
Although the therapeutic index of these immunotherapies should never be as unfavorable as for any of the cytotoxics listed above, the identification of biomarkers of maximal benefit is still critical (and the therapeutic index can still be unfavorable for selected immunotherapies such as high-dose interleukin-2). The important concept of immunogenic chemotherapy has been studied extensively in preclinical models, but regimen design based on these interactions has not been widely adopted, and it has not yet been incorporated into studies of immune checkpoint blockade.4
PD-1/PD-L1 Blockade vs Targeted Therapies
Is it possible that PD-1/PD-L1 axis blockade will reach a level of target specificity similar to that of imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumor, erlotinib for lung cancer carrying selected epidermal growth factor receptor gene mutations, and vemurafenib (Zelboraf) for melanoma with a BRAF-activating mutation? To this question, the answer is more likely no, since the mechanisms of action and of resistance are dramatically different between the molecular drivers and modifiers of tumor cell biology. So too is the immune system/tumor microenvironment, which involves many different cell types and demonstrates heterogeneity and plasticity over time and the local microenvironment. Interestingly, the overlap of molecularly targeted therapies and immunotherapies has been described for BRAF-mutated melanoma5 and to a lesser extent for combinations with inhibitors of the mediators of tumor angiogenesis.6
Predictors of Benefit
How can the activity of PD-1 axis blockade be predicted in order to select therapy for those patients most likely to benefit? Pretreatment factors are far more valuable than on-therapy or post-therapy correlates, although the latter often provide deep insights into mechanisms of action and acquired resistance. However, on-therapy and post-therapy tissue acquisition is also more challenging due to the likelihood of a lower willingness to undergo biopsy and worsened medical condition among patients with disease progression and to a paucity of residual tumor among patients responding well to therapy.
To date, only the expression of PD-L1 on tumor has been recognized to carry predictive value, but even this parameter is fraught with differences in assay techniques and suboptimal positive and negative predictive values. The co-localization at the invasive tumor margin of CD8 T cells expressing PD-1, cells expressing PD-L1, and a restricted T-cell receptor gene clonality among the infiltrating CD8 cells has recently demonstrated a strong association with response of melanoma to pembrolizumab (Keytruda)7; many other factors remain under investigation and are likely to differ among tumor types, stages, and patterns of organ involvement, as well as host germline genetics.
Overcoming Intrinsic and Acquired Resistance
One approach to optimize patient benefit may be the enhancement of tumor PD-L1 expression by one of several approaches, including the use of interferon gamma, which is believed to be the most important physiologic inducer of PD-L1 expression. Other strategies include altering gene expression with epigenetic agents such as demethylating therapy or histone deacetylase inhibitors or adding hypofractionated radiotherapy, which has immunoenhancing properties via multiple mechanisms.8
Combinations designed to overcome immunosuppressive signals in the tumor microenvironment or enhance cellular cytotoxicity by costimulation of effector T cells are not specific to PD-1 blockade but may provide important additive or synergistic effects. They include agonistic antibodies to the costimulatory molecules OX40, CD40, and CD137. Blocking negative microenvironmental signals can be achieved with inhibitors of indoleamine dioxygenase or tumor-associated macrophages, as well as the radiotherapy strategies mentioned here. Even combinations with cytokines, including interleukin-2 at lower doses than used as a single agent, are under investigation, in the hope of enhancing patient benefit while maintaining a favorable therapeutic index.
A Bright Future for Immunotherapy
Although most of the preclinical basis and clinical results summarized here have been most extensively seen in melanoma and lung cancer—the two diseases in which PD-1–blocking antibodies have regulatory approval—these principles (and the high likelihood of some important differences) will be valuable for the development of regimens for other malignancies. At the time this commentary was written, the clinicaltrials.gov website listed 54 actively recruiting studies with nivolumab (Opdivo) and 64 with pembrolizumab.
The importance of an immune response to cancer has been known for decades and preceded the widespread use of cytotoxic chemotherapy. However, it is only in the past 2 to 3 years that the potent and safe use of immunotherapy has finally achieved promise for melanoma and other malignancies. Patients and their physicians can look forward to a day when the morbidity and mortality of cancer are dramatically reduced by immunotherapy and the optimal use of this modality can be individualized to range from preventive interventions through surgical adjuvant therapy to curative systemic therapy for advanced disease. ■
Disclosure: Dr. Margolin reported no potential conflicts of interest.
References
1. Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015.
2. Robert C, Schachter J, Long GV, et al: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. April 19, 2015 (early release online).
3. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol 16:522-530, 2015.
4. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G: The secret ally: Immunostimulation by anticancer drugs. Nat Rev Drug Discov 11:215-233, 2012.
5. Cooper ZA, Reuben A, Amaria RN, Wargo JA: Evidence of synergy with combined BRAF-targeted therapy and immune checkpoint blockade for metastatic melanoma. Oncoimmunology 3:e954956, 2014.
6. Vanneman M, Dranoff G: Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 12:237-251, 2012.
7. Tumeh PC, Harview CL, Yearley JH, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014.
8. Demaria S, Pilones KA, Vanpouille-Box C, et al: The optimal partnership of radiation and immunotherapy: From preclinical studies to clinical translation. Radiat Res 182:170-181, 2014.
Dr. Margolin is Professor of Medicine (Oncology) at Stanford University Medical Center, Stanford, California.
