Immunotherapy Resistance
Shelly E. Hummert, PharmD
Clinical Oncology Pharmacist
Huntsman Cancer Institute, University of Utah
Salt Lake City, UT
In the last decade, approaches to using the immune system to treat cancer have exploded. Currently, immunotherapy is an important U.S. Food and Drug Administration–approved option for the management of melanoma, lung cancer, and renal cell carcinoma. Based on the results in these disease states, immunotherapy continues to be studied in a range of cancers and has the potential to become the backbone of treatment to effectively control cancer.
A benefit of immunotherapy is the possibility of a durable response. This has been attained with interleukin-2 and immune-modulating antibodies such as ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 inhibitor, and pembrolizumab and nivolumab, programmed death 1 (PD-1) inhibitors. In a study conducted by Postow, first-line therapy with ipilimumab in advanced melanoma was compared to combination therapy with ipilimumab and nivolumab in advanced melanoma.1 A median duration of response was not identifiable at the conclusion of the study because the majority of patients (75% of patients receiving ipilimumab alone and 82% of patients receiving combination therapy) continued to have an ongoing response.
However, the possibility of resistance to immunotherapy, as with any type of treatment, remains a concern. Ribas recently demonstrated that only 74% of patients who achieved an objective response with pembrolizumab maintained the response at 21 months, indicating that 26% of these patients experienced disease progression.2 Zaretsky and colleagues found similar results, with 36% of patients demonstrating disease progression after obtaining an objective response with pembrolizumab.3 The initial response to treatment and median progression around 21 months led the researchers to postulate that relapse was a result of clonal selection.
Zaretsky and colleagues compared tumor DNA samples at baseline and relapse in four patients. Of the four patients assessed, differences between the DNA samples were linked to loss of heterozygosity.3 Loss-of-function mutations in the Janus kinase 1 and 2 (JAK1 and JAK2) were identified in two of the four patients. These mutations were associated with the interferon-receptor pathway and were acquired through the loss of the wild-type chromosome and duplication of the mutated allele. Analysis of the baseline biopsies demonstrated response to interferon alfa, beta, and gamma, whereas analysis of the relapse biopsies demonstrated no response to interferon gamma. Interferon gamma is responsible for cell growth inhibition. These data suggest that loss of JAK mutations may lead to a decrease in antigen presentation and expression of programmed death–ligand 1 (PD-L1), enabling the tumor to evade recognition by the immune system.
An acquired resistance because of a mutation in the gene encoding beta-2-microglobulin (β2M), a component of the major histocompatibility complex class I, was identified in a third patient who developed relapsed disease in the Zaretsky trial.3 Antitumor T cells recognize antigens presented on cell surfaces by MHC class I molecules, which are limited or eliminated by mutations in β2M.4 Restifo and colleagues also concluded that the loss of β2M in five metastatic melanoma patients was a result of immunotherapy treatment and may be a mechanism of acquired immuno-
resistance.5
The fourth patient who developed relapsed disease did not have a loss of heterozygosity.3 However, neither the baseline nor the relapse biopsies expressed PD-L1, indicating the possibility of altered expression of interferon-inducible genes as an alternative mechanism of resistance.
Other possibilities for mechanisms of resistance that have been hypothesized include expression of suppressive factors, such as indoleamine 2,3-deoxygenase (IDO), a link of tumor suppressor gene loss to PD-L1 expression, and therapy-induced resistance. Therapy-induced resistance has been described as cases where patients relapse after having an initial response to immunotherapy, likely as a result of isolated or newly developed resistant tumor clones.6,7 These additional mechanisms of resistance are the reason for current studies on PD-L1 inhibitors (e.g., atezolizumab, avelumab, and durvalumab) as well as combination studies with IDO inhibitors (e.g., indoximod and epacadostat). As we discover more about pathways of resistance, combination therapy may hold promise for synergy to further improve immune function against cancer.
Data that currently exist on immunoresistance, especially in humans, are limited. However, several theories have been developed from data on the extensive number of patients who experience little to no benefit or have relapsed disease with immunotherapy. At this point, we are unable to detect which patients may have a durable response and which will have no response. As immunotherapy continues to be studied and approved for various cancer types, more patients will experience disease relapse after an initial response. This will provide a larger sample size to further evaluate immunoresistance by evaluating differences between baseline and relapse tumor DNA. It is important therefore that studies continue to compare biopsies to discover treatment options that will prevent or limit immunoresistance.
References
1. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017.
2. Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315(15):1600-1609.
3. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819-829.
4. Hicklin DJ, Wang Z, Arienti F, Rivoltini L, Parmiani G, Ferrone S. Beta2-microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma. J Clin Invest. 1998;101(12):2720-2729.
5. Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst. 1996;88(2):100-108.
6. Johnson TS, Munn DH. Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor tolerance. Immunol Invest. 2012;41(6-7):765-797.
7. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.