“Fundamental research — much of it done in Boston — has led to a shift in the scientific strategy for fighting some cancers, toward using drugs to activate a patient’s own immune system. An approach that was on the fringes of cancer therapy is suddenly the hottest trend in cancer drug development. On Monday, for example, Boston researchers presented data showing that nearly half of patients with advanced melanoma lived for two years after getting an experimental immune therapy called nivolumab, though multiple other therapies hadn’t worked for them. And drug companies have announced several deals recently to acquire companies developing immunotherapies. The frenzy of activity is an abrupt change for a field that had made big promises but failed to deliver for years.”
“The immune system has this blind spot by design – an immune system that has an ability to attack itself leads to autoimmune diseases, so as protection, it screens out its own tissue.
“For decades, scientists assumed that cancer was beyond the reach of the body’s natural defenses. But after decades of skepticism that the immune system could be trained to root out and eliminate these malignant cells, a new generation of drugs is proving otherwise.
“The treatment consists of infusing antibodies that enhance the immune system to recognize cancer cells and attack it. What’s more, since the immune system has a built-in memory, it continues to go after cancer cells, so the response can be longer lasting and more complete.
“The trick is that this treatment doesn’t work for everybody, and researchers don’t yet understand why. But when it does work, the results have been particularly impressive.”
In the past 2 years, cancer treatments known as immune therapies have become all the rage. However, they have actually been explored for decades, particularly in melanoma, and have produced some notable successes. Now, immune therapies are showing more and more promise for lung cancer. Continue reading…
In this article, we examine the current state of the art in lung cancer immunotherapy, including vaccines that specifically target lung tumor antigens and immune checkpoint antibodies such as antiprogrammed death 1 (anti-PD-1). Both approaches harness innate immunity against tumors by suppressing tumor-induced immune paresis.
The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. Our data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.
“Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is the first agent associated with a documented improved overall survival benefit in this patient population. A striking attribute of CTLA-4 blockade is the durability of objective responses, leading to speculation of a possible cure for some patients. Many tumor responses achieved with PD-1 and PD-L1 inhibition were durable in the phase I trials and were seen in a higher proportion of patients with melanoma than typically observed with ipilimumab. Biomarker development to identify the subset of patients with melanoma who will achieve durable clinical benefit with checkpoint blockade is critical; tumor PD-L1 expression has been promising in early studies. The contrast between unprecedented response rates but limited durability of responses achieved with BRAF and MEK inhibition in BRAFV600-mutated melanoma and the impressive durability but relatively low rate of response achieved with immune checkpoint blockade is striking. Preclinical data on potential synergies between CTLA-4/PD-1/PD-L1 inhibition and MAPK-targeted therapy is emerging, and combined immune checkpoint blockade and MAPK inhibition are being explored in clinical trials. Other promising approaches to increase the number of patients with melanoma who benefit from durable responses with immune checkpoint blockade include concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies.”
We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR.