Elucidating Additional Patient Subgroups Enhances Understanding of Cancer Biology

Robert L. Ferris, MD, PhD

In this issue ofThe Journal of Targeted Therapies in Cancer™ (JTT), 2 articles in particular impressed me as reflective of the evolution and development of therapeutic possibilities for patients with recurrent and metastatic epithelial cancers. Although the 2 may initially seem to have distinct focuses, it is now becoming apparent that combinatorial strategies harnessing conventional modalities such as radiation therapy (RT) and immune stimulatory approaches may have additional value for this population of patients.

The first article is a commentary on therapeutic, antigen-specific cancer vaccines. In the review we publish in this issue, a resurgence in the interest regarding cancer vaccines is described. For non—small cell lung cancer (NSCLC), large studies involving cancer vaccines targeting various tumor antigens that were found to be highly expressed in tumor cells have been conducted over the past decade. In general, these trials were negative from a standard clinical oncologic endpoint. With later subset analyses, however, it seemed that apparent benefit might manifest in particular retrospectively defined patient subsets, but this has not been validated in prospective trials, as the enthusiasm for cancer vaccines waned. Next, the well-known revolution in immune-based approaches, through targeting immune checkpoint receptors (ICRs) such as PD-1 and CTLA-4, inspired renewed interest in the oncology community for cancer immunotherapy. Of course, these approaches differ since cancer vaccines stimulate a broader and deeper repertoire of T-cell receptor–bearing, cancer-specific lymphocytes. Activating the T-cell receptor manifests as signal 1, and it results in stimulating and broadening the T-lymphocyte activation. The strength of the ICR targeting field is the recognition that negative regulatory signals are very common in cancer patients, and “taking off the brakes” is an effective strategy to reactivate endogenous cancer antigen-specific lymphocytes. This approach is generally perceived as targeting signal 2, of improving hosting relation or alleviating co-inhibition. Therefore, the resurgence in vaccines is based on the recognition that not all patients will respond to “signal 2,” via ICR targeting through PD-1, CTLA-4, or other ICRs. Thus, increasing the number of patients with antigen-specific T lymphocytes may prime that patient’s immune system to respond to ICR-based immunotherapies. A number of interesting and creative strategies or cancer vaccinations have been tested in recent years and can now return to the clinical arena for combinatorial approaches with ICR-based therapies.

The second article of interest includes the targeting of oligometastatic disease through locally ablative therapies (LATs). Bauml and colleagues report data using LAT for oligometastatic disease (generally 1 to 5 metastatic lesions), reviewing the different approaches that have been utilized for this increasingly common, difficult-to-treat population. While immunotherapy alone may be utilized, conventional LAT may have direct antitumor effects or, more likely, may provide an additional therapeutic mechanism for triggering a benefit of systemic cancer immunotherapy. Given the excitement for the recent PACIFIC trial leading to the FDA approval of durvalumab for NSCLC in the adjuvant setting, systemic immunotherapy has the potential to combine with LAT, targeting radiographically physical metastatic lesions with antigen-specific reactivation of microscopic undetectable disease.