Viral infections often gain access to the body of their host by exploiting areas of natural vulnerability, such as the semipermeable surfaces of mucosal tissues which are adapted for adsorption of nutrients and other diffusible molecules. Once the microbes have crossed the epithelial barrier, they can disperse to other tissues where eradication may not be possible. The best opportunity for successful immune intervention is immediately after infection while the pathogen is confined to a localized area of the body. Cytotoxic T lymphocytes (CTL) which reside at the site where the infection begins can make an important contribution to immunity by reducing early dissemination of the infection. Because the lungs provide easy access points for many pathogens to enter the body, they require protection from many complementary mechanisms, including pathogen-specific cytotoxic T cells. In this study we show that an enduring response to pathogen-derived peptide antigens facilitates sustained surveillance of the lungs by pathogen-specific CTL during the recovery from influenza virus infection. Our studies show that these processed peptide antigens reinforce expression of two homing receptors (CD69 and CD103) which help recently activated virus-specific CTL colonize the lungs during a mild inflammatory response. We suggest that this requirement for prolonged antigen presentation to reinforce local CTL responses in the lungs explains why protective cellular immunity quickly declines following influenza virus infection and other viral infections that enter the body via mucosal tissues.

In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.

The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.

Therapeutic cancer vaccines have gained significant popularity in recent years as new approaches for specific oncologic indications emerge. Three therapeutic cancer vaccines are FDA approved and one is currently approved by the EMA as monotherapy with modest treatment effects. Combining therapeutic cancer vaccines with other treatment modalities like radiotherapy (RT), hormone therapy, immunotherapy, and/or chemotherapy have been investigated as a means to enhance immune response and treatment efficacy. There is growing preclinical and clinical data that combination of checkpoint inhibitors and vaccines can induce immunogenic intensification with favorable outcomes. Additionally, novel methods for identifying targetable neoantigens hold promise for personalized vaccine development. In this article, we review the rationale for various therapeutic combinations, clinical trial experiences, and future directions. We also highlight the most promising developments that could lead to approval of novel therapeutic cancer vaccines.