Trial watch

Abstract

Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8+ cytotoxic T lymphocytes, Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4+CD25+FOXP3+ regulatory T cells, Th2 CD4+ T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that—at least in some clinical settings—the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies.

Interleukin-35 Limits Anti-Tumor Immunity

“…CD4 + CD25 + Tregs are frequently increased in the periphery of cancer patients and specifically recruited to malignant sites, where they actively inhibit infiltrating cytotoxic T lymphocytes (CTLs) (Cao, 2010). Conversely, CD8 + T cell infiltration is a positive prognostic indicator in many tumor types including breast, prostate, cervical, melanoma, and others (Galon et al, 2013; Senovilla et al, 2012). Successful anti-tumor responses require potent CD8 + CTL induction and CD4 + T cell help, yet the immune system is critically involved in promoting tumorigenesis by blocking anti-tumor immunity via Tregs.…”

Trial Watch: Peptide-based anticancer vaccines

“…In addition, as for many other (immuno)therapeutic interventions, it will be crucial to identify biomarkers that reliably predict the propensity of individual patients to respond to peptide-based anticancer vaccines. [269][270][271][272][273] Time will tell whether these avenues are those that lead to the approval of peptide vaccination by international regulatory agencies for use in cancer patients.…”

Trial watch: Naked and vectored DNA-based anticancer vaccines

“…69,[75][76][77] In addition, progressive tumors often establish potent immunosuppressive networks that limit the efficacy of DNA-based vaccines and several other forms of immunotherapy. [78][79][80][81][82][83][84] These immunosuppressive circuitries operate both locally and systemically and generally develop along with natural tumor progression, although the presence of an accrued immune reaction, such as that elicited by TAA-targeting vaccines, is expected to accelerate this process. 85,86 The emergence of antigen-loss tumor variants and/ or the establishment of local and systemic immunosuppression explains why -in spite of promising preclinical resultsmost DNA-based anticancer vaccines are not efficient in patients when employed as standalone immunotherapeutic interventions.…”