Resistance to immunotherapy: The elusive routes of immune escape
Achieving a durable clinical response is the ultimate goal in immuno-oncology clinical trials. With immunotherapies showing long-lasting, unprecedented responses in cancer indications such as melanoma and Non-Small Cell Lung Cancer (NSCLC), these immune-boosting drugs seem to be displaying genuine advances in attaining significant and sustained response rates. Nonetheless, just as with targeted therapies, immuno-oncology drug resistance can manifest via both primary and acquired mechanisms, to defy elimination of cancerous cells. In primary resistance, a patient never responds to therapy; with acquired resistance a patient may initially respond, but this response is often short-lived with eventual relapse. Investigators have unraveled both intrinsic and extrinsic cellular factors playing major roles in resistance (Sharma et al. 2016). For example, lack of antigenic mutations illustrates a tumor cell intrinsic mechanism, as cancers with low mutational burden (such as ovarian, breast, and others) may show limited benefit from immunotherapy. Extrinsic factors include components of the tumor microenvironment such as regulatory T cells (Tregs) that exert suppressive effects on the immune system. Tregs are known to regulate autoimmune disease, but in the context of the tumor microenvironment these cells play a major role in inhibiting antigen specific T-cells.
B2M: A particularly tricky culprit in acquired resistance
Acquired resistance is an especially devious mechanism as it provides patients with false hope as they initially experience clinical response, but ultimately the disease progresses. One reoccurring mechanism reported in the literature is loss of Beta-2 Microglobulin (B2M). B2M is present on all nucleated cells and serves as a membrane protein component of the Class I Major Histocompatibility Complex (MHC). Further, B2M is fundamental in antigen presentation as it assists in folding and transport of peptides to the surface of the cell. Without proper peptide presentation on MHC, cytotoxic CD8+ T cells cannot recognize these non-self or neoepitopes to become activated.
In early work (Hicklin et al. 1998), researchers demonstrated the importance of various B2M mutations in several melanoma cell lines, as the loss of functional transcripts was shown. Transfection of wild-type B2M into these cell cultures restored MHC Class I presentation. Moreover, pioneering work by Rosenberg and colleagues (Restifo et al. 1996) in melanoma patients receiving autologous tumor infiltrating lymphocytes and IL-2, first showed loss of B2M as a result of immunotherapy. They were able to confirm their hypothesis, as archival tissue available from three of the five melanoma patient samples was B2M positive prior to treatment (while exhibiting loss of B2M subsequent to treatment). In addition to Adoptive Cell Therapy (ACT), evidence of B2M loss has also been revealed as an acquired resistance mechanism to other forms of immunotherapy, such as Checkpoint Modulators. Last year, work published in the New England Journal of Medicine (Zaretsky et al. 2016) highlighted that a patient receiving anti-PD-1 treatment acquired a 4 base pair deletion in exon 1 of the B2M gene. Results from immunohistochemistry staining determined the definitive loss of MHC Class I molecules after treatment.
B2M strikes again
An exciting avenue in immunotherapy has been the current rapid and steadfast progression in next generation cancer vaccine development: personalized, neoantigen-based therapies. In July, the results from the first in human clinical trials were published and showed the promise that these therapeutics hold (Sahin et al. 2017 and Ott et al. 2017). Interestingly, Sahin and colleagues also deliver insight into acquired resistance mechanisms of these latest therapies. As has been previously shown with both ACT and Immune Checkpoint blockade treatment, using an RNA-based neoantigen vaccine approach in melanoma patients, one patient developed a B2M deficiency due to a deletion and inversion event after receiving treatment. Although anti-PD-1 treatment was initiated, the potency of this acquired tumor escape mechanism was still exhibited as disease progressed.
Conquering an indefinable “enemy”
Despite the complexity of the problem at hand, how do we really defeat these resistance mechanisms in the war against cancer? As many suggest, perhaps the solution is determining the most rational, effective combination therapy approach.
This involves continued investment in pre-clinical and clinical translational research to further understand the pathways that tumor cells use to evade immune surveillance. Having data points at both pre- and post- treatment is also essential to have a more complete picture of the biology of tumor evolution during the course of treatment. Also published last year, Anagnostou et al. detailed the mutational landscape changes in the course of anti-PD-1/anti-CTLA-4 therapy in NSCLC patients, to determine the overall alteration in somatic variants and neoantigen load prior to and at time of progression. More studies like these, as well as “fine- tuning” of these studies may reveal shared mechanisms in patient populations to tailor clinical plans for treatment. Innovations in monitoring these critical genomic alterations using liquid biopsies also represent clever ideas for continual improvement in clinical outcomes. Enabled by elegantly designed clinical trials and translational research, as well as the appropriate technologies to comprehensively bridge developmental stages, we are beginning to truly conquer an elusive “enemy” using a wealth of high-content patient data.