Cancer network recently published an interview with Jesse Zaretsky who is working as a research scientist in Antonio Ribas’ group at UCLA (1). Jesse and Prof. Ribas recently published in NEJM about one (out of probably many) possible mechanisms of resistance against immunotherapy in melanoma. I wrote previously about what a smart approach it is to target the escape from immune-surveillance as an anti-cancer treatment strategy. Yet, here we are realizing that cancer is – again – finding ways to bypass this approach as well.
There are several hypotheses how resistance to immunotherapy could happen. 1) Tumors are intrinsically resistant meaning immunotherapy never has an effect in these patients e.g. necessary T cells are not present in the tissue around the tumor or antigen presentation is lacking. 2) Immunotherapy is effective for a certain time period (sometimes years), tumors shrink or disappear but grow again or reappear at a later time because cancer cells are able to up- or downregulate specific pathways to bypass immunotherapy or 3) since tumors are heterogeneous most of the time, therapy works in one part of the tumor but not in another and after a while the unaffected part grows beyond the limits of the original tumor taking over space that has become available. In other words, the effects of immunotherapy are dynamic spatially and over time leaving room for several mechanisms of resistance.
In order to find mechanisms that evolve during immunotherapy leading to resistance, the Zaretsky/Ribas research team analyzed tissue samples taken from melanoma patients participating in a phase I study before immunotherapy with an anti PD-1 antibody has begun and at time of progression or relapse.
78 melanoma patients participated in the trial, 42 responded to the antibody treatment of whom 15 recurred. Conditions for participation in this translational research project were stringent: Pts had to have long-term objective response (≥6 months), acquired resistance visible as a new lesion or the primary tumor had to regrow and sufficient tumor tissue material had to be available for whole-exome sequencing.
The paper focused on two patients that both had, during treatment with the immunotherapeutic, acquired mutations in two different isoforms of Janus kinases (JAK1 and JAK2). While these are very small number of patients, the results are hypothesis-creating and worth pursuing in a prospectively conducted (phase II) trial.
What did they find? Jesse was able to show that in both patients either JAK had lost its function due to mutations. What does this mean? In very simple words: JAK function is associated with interferon signaling, which is required for proper antigen presentation on a cancer cell’s surface so that this cell can be recognized as cancerous by the immune system. Thus, cancer cells without functional JAK can have a selective growth advantage bypassing and escaping from immune-surveillance.
What are potential implications of these findings? Immunotherapy is a very effective treatment for a significant group of melanoma patients but not effective forever. Some patients may progress because their cancer finds a path to present less or no antigen that triggers the immune system. One mechanism uses loss of function of the JAK pathway making mutations in the JAK gene a potential biomarker of resistance that could be used in the future. Monitoring and detection of this biomarker might be possible through a blood draw using ctDNA instead of DNA from tissue collected by a biopsy, which is less invasive and patient friendlier. But this is just my personal hope and speculation.
In addition, these data indicate that combining immunotherapy with other agents or therapies might be necessary in some patients to prolong the response to therapy and to prevent resistance from happening. This has been postulated by many investigators and is currently tested in numerous different clinical trials and will be subject of my next post.
The here-discussed research has great value providing the research community with a new potential biomarker of resistance against immunotherapy. It is the second molecular biomarker that has been proposed and many others will surely follow as more and more knowledge is collected in this challenging field. Another mechanism for cancer cells to become resistant is gene silencing. In this case, regulators’ activity like that of JAK is “turned off ” gene silencing through histone deacetylation or methylation. Trials combining HDAC and DNMT inhibitors with PD1 antibodies are in process. Combining IO and epigenetics is a very interesting approach presented by Dr. Velcheti in an educational session at ASCO 2016 showing the numerous opportunities in this field.
- Zaretsky, J. M. and Ribas, A. et al. (2016) Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. NEJM Epub ahead of print.
- ASCO 2016 Educational Session “Tumor Immunology: Basic Biology for Clinical Practice” by Vamsidhar Velcheti from Cleveland Clinic.