W. Pao

Genomic analysis of 63,220 tumors reveals insights into tumor uniqueness and targeted cancer immunotherapy strategies

BackgroundThe integration of genomics with immunotherapy has potential value for cancer vaccine development. Given the clinical successes of immune checkpoint modulators, interest in cancer vaccines as therapeutic options has been revived. Current data suggest that each tumor contains a unique set of mutations (mutanome), thus requiring the creation of individualized cancer vaccines. However, rigorous analysis of non-individualized cancer immunotherapy approaches across multiple cancer types and in the context of known driver alterations has yet to be reported. We therefore set out to determine the feasibility of a generalizable cancer vaccine strategy based on targeting multiple neoantigens in an HLA-A/B subtype-directed manner.MethodsA cancer gene-focused, hybrid capture-based genomic analysis was performed on 63,220 unique tumors. Neoantigens were predicted using a combined peptide processing and MHC-I binding prediction tool (IEDB) for all recurrent (>10 tumors) missense alterations and non-frameshift indels for the two most common HLA-A/B subtypes in North American/European populations.ResultsDespite being overwhelmingly unique overall, many mutanomes (~45%) contain at least one mutation from a set of ten mutations chosen to maximize the number of unique tumors. This held true for tumors driven by KRAS G12C (n = 1799), PIK3CA E545K (n = 1713), or EGFR L858R (n = 478) alterations, which define distinct sample subsets. We therefore hypothesized that sets of carefully selected mutations/neoantigens may allow the development of broadly applicable semi-universal cancer vaccines. To test the feasibility of such an approach, antigen processing and MHC-I binding prediction was applied for HLA subtypes A*01:01/B*08:01 and A*02:01/B*44:02. In tumors with a specific HLA type, 0.7 and 2.5% harbored at least one of a set of ten neoantigens predicted to bind to each subtype, respectively. In comparison, KRAS G12C-driven tumors produced similar results (0.8 and 2.6% for each HLA subtype, respectively), indicating that neoantigen targets still remain highly diverse even within the context of major driver mutations.ConclusionsThis “best case scenario” analysis of a large tumor set across multiple cancer types and in the context of driver alterations reveals that semi-universal, HLA-specific cancer vaccine strategies will be relevant to only a small subset of the general population. Similar analysis of whole exome/genome sequencing, although not currently feasible at scale in a clinical setting, will likely uncover further diversity.

Molecular characteristics of non-small cell lung cancer (NSCLC) patients sensitive to gefitinib

7025 Background: Gefitinib (Iressa), a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK), induces objective regressions in 9-18% of NSCLC patients. Bronchioloalveolar histology and smoking history may predict response to gefitinib (Shah, NT, Proc ASCO 2003). Molecular studies to date have not shown any correlation between EGFR status and sensitivity to gefitinib (Bailey LR, Proc AACR 2003). To determine molecular characteristics predictive of sensitivity, we undertook selected analyses in gefitinib-sensitive and -refractory patients. METHODS Unstained slides or pathology blocks were collected on an IRB-approved protocol from 54 of 139 consecutive NSCLC patients treated at MSKCC with single agent gefitinib from 09/98 -11/02. Immunohistochemistry was performed on anonymized samples for total EGFR, the putative target of gefitinib; HER2/NEU, an EGFR family member whose co-expression may predict poorer outcome in NSCLC; phospho-AKT, an activated downstream signaling molecule that may confer resistance to gefitinib; and p53, a tumor suppressor gene frequently altered in NSCLC. Staining was graded by 2 pathologists blinded to clinical variables and outcomes. RESULTS The status of EGFR, HER2, p-AKT, and p53 are given in the table below. Among 20 patients whose tumors were EGFR(+) and HER2(+), 9 were gefitinib-sensitive; by contrast, only 1 of 8 patients whose tumors were negative for both markers was sensitive (p=0.19). CONCLUSIONS We found no relationship between total EGFR, p-AKT or p53 and sensitivity to gefitinib. HER2 expression (63%) was higher than that usually reported in NSCLC. The high percentage (80%) of HER2-positive tumors among gefitinib-sensitive patients warrants confirmation in a larger series, and strategies to block concurrently both EGFR and HER2 may be clinically useful. Studies on p-EGFR, p-MAPK, and PTEN are in progress. [Figure: see text] [Table: see text].