Barbara Burtness, MD
Testing of immune checkpoint inhibition in cancer types in which immune exhaustion may play a role has become a priority in oncology. Substantial evidence exists that a subset of squamous cell cancers of the head and neck display phenotypic changes that predict activity for immune checkpoint inhibitors, treatments that interfere with PD-1 or CTLA-4-dependent immune tolerance. CD8+ tumor-infiltrating lymphocytes are associated with improved survival after chemoradiation for both human papillomavirus (HPV)-associated and HPV-negative head and neck cancer. Cancer antigens may be present in the head and neck either because of mutations that lead to unique protein structures (neoantigens) or from the expression of viral antigens in HPV-associated cancers. The PD-1 inhibitor pembrolizumab was tested in patients with PD-L1–expressing head and neck cancer. The overall response rate (ORR) to pembrolizumab was 19.6% (95% CI, 10.2%-32.4%), with the median duration of response not reached at 8+ to 41+ weeks. Data supporting the activity of immune checkpoint inhibition in squamous cancer of the head and neck have also been obtained with the anti-PD-1 antibody MEDI4736. The ORR for this agent in a multitumor-type study was 11%; among PD-L1– positive patients, 4 of 17 (24%) responded compared with 1 of 33 (3%) PD-L1–negative patients. A large number of ongoing or recently completed trials are reviewed.
The recent revolution in our understanding of the importance of the immune response to cancer has led to remarkable new therapies for melanoma, renal cell cancer, and non–small cell lung cancer. Responses to immune checkpoint inhibitors are seen in cancers that are quite varied, and the responses can be of long duration. For this reason, rapidly moving to study immune checkpoint inhibition in additional cancer types in which immune exhaustion may play a role has become a priority in oncology.
Substantial evidence exists that a subset of squamous cell cancers of the head and neck (SCCHN) display phenotypic changes that predict activity for immune checkpoint inhibitors.1
The endogenous T-cell compartment recognizes peptide epitopes displayed on major histocompatibility complexes on surfaces of malignant cells; thus, both antigen expression within tumors and immune cell infiltration of the tumor and its environment are important to characterize. CD8+ tumor-infiltrating lymphocytes (TILs) are associated with improved survival after chemoradiation for both human papillomavirus (HPV)-associated and HPV-negative SCCHN.2
Nonmutated proteins to which T-cell tolerance is incomplete because of a restricted tissue expression pattern may act as cancer rejection antigens. An additional class of antigens, referred to as neoantigens, are formed by peptides not coded by the normal human genome, but rather created by tumor-specific DNA alterations.
Linnemann and colleagues used a cancer exome–based approach to identify neoantigens that can be recognized by T cells.3,4
Mutations that generate a novel protein sequence were identified and potential MHC-binding peptides were predicted for each. T-cell reactivity against the predicted neoantigens was then determined, revealing that only a minority of novel peptides resulting from mutation in cancers are immunogenic; however, higher mutational burden is predicted to result in greater expression of immunogenic antigens, perhaps explaining the high activity of immune checkpoint inhibition in such hypermutable states as microsatellite instable colon cancer.5
Given the frequency of loss of tumor suppressor functions and the resulting known high mutational burden of HPV-negative SCCHN, the expression of mutationally associated neoantigens is predicted to be high in these cancers. APOBEC3B cytosine deaminase activity is induced in virally infected cells, and analysis of The Cancer Genome Atlas SCCHN samples reveals a mutagenesis pattern consistent with APOBEC-mediated effects, raising the possibility that neoantigens are increased in HPV-associated cancers as well.6