The Importance of Biomarkers for Cancer Immunotherapy

The Journal of Targeted Therapies in Cancer2016 April
Volume 5
Issue 2

Immunotherapy for cancer has been studied in the laboratory and in early-phase trials for decades. Larger trials were not often successful enough, though in the last five years, a revolution has centered around the clinical success of checkpoint blockade with CTLA-4 and PD-1 antibodies.


Immunotherapy for cancer has been studied in the laboratory and in early-phase trials for decades. Larger trials were not often successful enough to lead to incorporation of immune-based approaches into standard of care. In the last five years, a revolution has occurred, centered around the clinical success of checkpoint blockade with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) antibodies. These and other newly licensed biologic drugs are promoting potent and durable clinical responses in patients including those with tumors not historically considered “immunogenic.” However, there are still toxicities associated with immunotherapies, and the majority of treated patients do not have durable responses; hence, there is a critical need for standardized and validated biomarkers that yield actionable insights into immunotherapy efficacy.


Biomarkers for cancer immunotherapy have been sought for decades. The use of Interleukin-2 (IL-2) for melanoma and renal cancer can lead to durable complete responses, but in a small minority of patients and with considerable toxicity.1Interferon-alpha for melanoma in the adjuvant setting can reduce the frequency of recurrence, but the effect is not very large, there are significant toxicities, and the regimen is a year long.2A test to identify patients who benefit from these approaches, a predictive biomarker, would be valuable to avoid ineffective therapies and toxicities for patients.

Biomarker Types

With the recent clinical successes of cancer immunotherapy comes the increasingly urgent need to identify patients who can benefit from immunotherapy interventions. The optimal biomarker would be a simple blood test that would accurately identify patients who could benefit from available therapies. Other types of biomarkers that would be of utility are assays that would indicate soon after treatment whether or not a patient was benefiting from a therapy in time to change treatment plans. They would also provide a measure of a treatment’s mechanism of action, which would yield important information to understand and optimize approaches and rationally define combinations. For small-molecule signal transduction pathway inhibitors such as vemurafenib, the assay is simple: does the tumor express a mutated BRAF gene, yes or no? For biologics that modulate the immune system, the biomarker question is more complex.

Prognostic Biomarkers

While there are many candidate biomarkers of interest, most are prognostic biomarkers that suggest a subset of patients who are more likely to have a better outcome after the initiation of treatment. Candidate prognostic biomarkers include inducible T-cell co-stimulator (ICOS) upregulation on T cells and reduced CD8+ T cell to regulatory T cells (Treg) ratio in a tumor infiltrate after CTLA-4 blockade3-5, PD-L1 expression on tumors before PD-1 blockade treatment6, myeloid-derived suppressor cell (MDSC) frequency7, CD3/CD8/CD45RO memory T cell infiltrate into tumors (the “Immunoscore”)8-10, tumor mutation burden11,12, and others. These biomarkers are measured in blood and tumor samples and are undergoing further testing, standardization, and validation.

To summarize the state of the field, identify hurdles, and make recommendations to move the field of immunotherapy biomarkers forward, the Society for Immunotherapy of Cancer (SITC)13-17 reconvened the Biomarkers Task Force Steering Committee18to create four working groups to address four key areas in biomarkers science and assay development. Each group is led by leaders in the area and consists of experienced members of academia, industry, and government. Each working group is completing a white paper to appear in theJournal for ImmunoTherapy of Cancer (JITC).19The topics are: 1) assay standardization and validation (Magdalena Thurin, PhD, and Giuseppe Masucci, MD, PhD); 2) novel biomarker technologies (Jianda Yuan, MD, PhD); 3) immune regulation and high-throughput approaches (David F. Stroncek, MD); and 4) tumor microenvironment and baseline measures (Sacha Gnjatic, PhD). In addition to a summary meeting on April 1, 2016, at NCI with a meeting report to follow inJITC, the Task Force has published a series of biomarker technology primers to concisely describe promising technology approaches to biomarker identification.20-26

While the field of cancer immunotherapy has had a great number of FDA approvals for antibody checkpoint molecule blockade therapeutics for melanoma, lung cancer, and other tumors (with more expected) as well as approved virus therapeutics27-29, future breakthroughs in validated biomarker development will be a critical next step.


  1. Rosenberg SA. IL-2: the first effective immunotherapy for human cancer.J Immunol. 2014;192(12):5451-5458. doi: 10.4049/jimmunol.1490019.
  2. Tarhini AA, Gogas H, Kirkwood JM. IFN -α in the treatment of melanoma.J Immunol. 2012;189(8):3789-3793. doi: 10.4049/jimmunol.1290060.
  3. Liakou CI, Kamat A, Tang DN, et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients.Proc Natl Acad Sci U S A. 2008;105(39):14987-14992. doi: 10.1073/pnas.0806075105.
  4. Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.Proc Natl Acad Sci U S A. 2008;105(8):3005-3010. doi: 10.1073/ pnas.0712237105.
  5. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial.JAMA. 2014;312(17):1744-1753. doi: 10.1001/jama.2014.13943.
  6. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012;366(26):2443-2454. doi: 10.1056/NEJMoa1200690.
  7. Walter S, Weinschenk T, Stenzl A, et al. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival.Nat Med. 2012;18(8):1254-1261. doi: 10.1038/nm.2883.
  8. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.Science. 2006;313(5795):1960-1964.
  9. Mlecnik B, Bindea G, Angell HK, et al. Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability.Immunity. 2016;44(3):698-711. doi: 10.1016/j.immuni.2016.02.025.
  10. Galon J, Pages F, Marincola FM, et al. Cancer classification using the Immunoscore: a worldwide task force.J Transl Med. 2012;10:205. doi: 10.1186/1479-5876-10-205.
  11. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer.Nature. 2013;500(7463):415-421. doi: 10.1038/nature12477.
  12. Le DT,Uram JN, Wang H,et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.N Engl J Med. 2015;372(26):2509-2520. doi: 10.1056/ NEJMc1510353#SA1.
  13. Keilholz U, Weber J, Finke JH, et al. Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy.J Immunother. 2002;25(2):97-138.
  14. Lotze MT, Wang E, Marincola FM, et al. Workshop on cancer biometrics: identifying biomarkers and surrogates of cancer in patients: a meeting held at the Masur Auditorium, National Institutes of Health.J Immunother. 2005;28(2):79-119.
  15. Butterfield LH, Disis ML, Fox BA, et al. A systematic approach to biomarker discovery; preamble to “the iSBTc-FDA taskforce on immunotherapy biomarkers.”J Transl Med. 2008;6:81. doi: 10.1186/1479-5876-6-81.
  16. Butterfield LH, Disis ML, Khleif SN, Balwit JM, Marincola FM. Immuno-oncology biomarkers 2010 and beyond: perspectives from the iSBTc/SITC biomarker task force.J Transl Med. 2010;8:130. doi: 10.1186/1479-5876-8-130.
  17. Butterfield LH, Palucka AK, Britten CM, et al. Recommendations from the iSBTc-SITC/FDA/NCI Workshop on Immunotherapy Biomarkers.Clin Cancer Res. 2011;17(10):3064-3076. doi: 10.1158/1078-0432.CCR-10-2234.
  18. Butterfield LH, Disis ML, Fox BA, Khleif SN, Marincola FM. Preamble to the 2015 SITC immunotherapy biomarkers taskforce.J Immunother Cancer. 2015;3:8. doi: 10.1186/s40425-015-0052-6.
  19. Yuan J, Hegde PS, Clynes R, et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy.J Immunother Cancer. 2016;4:3. doi: 10.1186/s40425-016-0107-3.
  20. Kirsch I. Immune monitoring technology primer: immunosequencing.J Immunother Cancer. 2015;3:29. doi: 10.1186/s40425-015-0076-y.
  21. Janetzki S. Immune monitoring technology primer: the enzyme-linked immunospot (Elispot) and Fluorospot assay.J Immunother Cancer. 2015;3:30. doi: 10.1186/s40425-015-0074-0.
  22. Hawtin RE, Cesano A. Immune monitoring technology primer: Single Cell Network Profiling (SCNP).J Immunother Cancer. 2015;3:34. doi: 10.1186/s40425-015- 0075-z.
  23. Maecker HT, Harari A.Immune monitoring technology primer: flow and mass cytometry.J Immunother Cancer. 2015;3:44. doi: 10.1186/s40425-015-0085-x.
  24. Dobbin KK. Immune monitoring technology primer.J Immunother Cancer. 2015;3:40. doi: 10.1186/s40425-015-0086-9.
  25. Kleen TO, Yuan J. Quantitative real-time PCR assisted cell counting(qPACC)for epigenetic-based immune cell quantification in blood and tissue.J Immunother Cancer. 2015;3:46. doi: 10.1186/s40425-015-0087-8.
  26. Cesano A. nCounter(®) PanCancer ImmuneProfiling Panel(NanoString Technologies, Inc., Seattle, WA).J Immunother Cancer. 2015;3:42. doi: 10.1186/ s40425-015-0088-7.
  27. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma.J Clin Oncol. 2015;33(25):2780-2788. doi: 10.1200/JCO.2014.58.3377.
  28. Yuan J, Wang E, Fox BA. Immune Monitoring Technology Primer: protein microarray (‘seromics’).J Immunother Cancer. 2016;4:2. doi: 10.1186/s40425- 016-0106-4.
  29. Stack EC, Foukas PG, Lee PP. Multiplexed tissue biomarker imaging.J Immunother Cancer. 2016;4:9. doi: 10.1186/s40425-016-0115-3.
Related Videos
Related Content