Advances in adoptive cell therapies and immune checkpoint blockades are fueling a renaissance in cancer immunotherapy, recently recognized by the journal Science as 2013’s “scientific breakthrough of the year”. But experts say that realizing the full potential of this treatment modality will ultimately involve therapeutic combinations to overcome the different mechanisms with which tumors and their microenvironments hijack patients’ immune systems.
Immunotherapy has been described as a “fourth weapon” in oncology’s arsenal—a class of treatments that, unlike traditional chemotherapy, radiotherapy, or surgery, includes agents designed to enlist the patient’s immune system rather than attacking tumors directly.1
Early immunotherapies did not yield dramatic clinical improvements, partly because of increasing genomic instability and genetic heterogeneity as tumors progress.2 But now, the field is enjoying a renaissance, thanks to advances in cancer vaccines and cell-based therapies, immune checkpoint blockades, and monoclonal antibodies (mAbs)—and importantly, novel combination therapies involving mAbs.2,3
For some patients, the immunotherapy benefits have been dramatic—dramatic and promising enough that the journal Science departed in December 2013 from a tradition of focusing on nonclinical research to name cancer immunotherapy as “the breakthrough of the year”.1,3 Anecdotal reports abound of patients with advanced and metastatic tumors surviving several years following immunotherapy.3
The natural immune system surveillance of the human body detects and frequently destroys nascent tumors, recognizing tumor-associated antigens on cancer cells, or forcing tumors into immune-mediated latency.2 But recent research has also revealed mechanisms of immune system evasion by tumors in some cases, including the downregulation of tumor-associated antigens.2 MAb therapies targeting tumor-associated antigens like human epidermal growth factor receptor 2 and epidermal growth factor receptor inhibit oncogene signaling and promote tumor cell cytotoxicity.2 However, mAbs have frequently exhibited insufficient immune activation and sustained efficacy in the face of tumor immune suppression and genomic instability, and efficacy can be lost as tumor-associated antigens are lost.2
Tumors’ escape mechanisms also include the hijacking of immune functions to promote tumor progression, such as increased secretion of immunosuppressive cytokines and inhibitory immune checkpoint molecules.2 Immune system cell infiltration of the tumor microenvironment can promote or slow tumor progression. The ratio of dendritic to T cells, for example, climbs in advanced tumors.4 Dendritic cells induce T-cell expansion in early-stage tumor microenvironments but those same cells can turn on patients, suppressing T-cell expansion in more advanced tumors.4
The goal of immunotherapy is ultimately to re-establish immune system antitumor vigilance and to inhibit tumor and tumor-microenvironment immunosuppression. Broadly speaking, there are four classes of immunotherapy: targeted antibodies like the cytotoxic T-lymphocyte antigen 4 (CLTA-4)-immune checkpoint blockade agent ipilimumab; adoptive cell transfers; cancer vaccines, including autologous dendritic cells loaded with tumor antigens; and nonspecific immune system stimulation with cytokines like recombinant human interleukin-2 (IL-2), a longstanding immunotherapy for patients with advanced melanoma and renal cell carcinoma (RCC; Table 1).
Table 1. Current Immunotherapy Strategies
|CTLA-4 immune checkpoint blockade (eg, ipilimumab)||Late-stage melanoma (ipilimumab FDA-approval, 2011)|
|PD-1 immune checkpoint blockade (eg, nivolumab, lambrolizumab)||Melanoma, RCC, NSCLC, hematologic malignancies (phase 1 to phase 3 trials)|
|Anticancer vaccines (eg, Sipuleucel-T)||All cancer types (Sipuleucel-T received FDA approval in 2010 for treatment of metastatic hormone-resistant prostate cancer)|
|Dendritic autologous cell-based vaccines (including patient-specific)||All cancer types (phase 1 to phase 3 trials)|
|MAGE-3 protein vaccine||NSCLC (phase 3 trial)|
|Idiotype antibodies (patient-specific tumor-derived antibodies plus GM-CSF)||Follicular lymphoma (phase 3 trial)|
|Nonspecific immune stimulation (eg, cytokine IL-2, IFNα)||Melanoma and RCC (phase 1 to phase 2 trials; FDA-approved high-dose IL-2 for advanced RCC in 1992|
Abbreviations: CTLA-4, cytotoxic T-lymphocyte antigen 4; FDA, US Food and Drug Administration; PD-1, programmed cell death protein 1; RCC, renal cell carcinoma; NSCLC, non-small cell lung cancer; MAGE-3, melanoma antigenic epitope 3; GM-CSF, granulocyte macrophage colony-stimulating factor; IL-2, interleukin-2; IFNα, interferon-alpha.