Autoantibodies to tumor-derived neoepitopes as biomarkers and immunoPET agents for the early detection of small cell lung cancer

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Project Summary/Abstract Small-cell lung cancer (SCLC) kills over 30,000 Americans every year and has a dismal 5-year overall survival rate of less than 7%. However, SCLC outcomes are greatly improved by early detection and intervention, with a nearly 50% 5-year survival rate for patients diagnosed at an early stage. These discrepant outcomes indicate that, by far, the majority of SCLC cases are diagnosed at later stages at which tumors rapidly become resistant to therapy, with death quickly following. Thus, an effective early detection strategy is necessary that both identifies cancer in people at high risk and facilitates non-invasive imaging that can confirm and delineate small tumors to guide surgical resection and treatment. We have found that autoantibodies (AAb) are present in the plasma of essentially all SCLC patients (much more common than in other major cancers) and have validated at least 7 AAb-identified neoantigens expressed by SCLC tumors that can be exploited as highly cancer-specific early detection biomarkers and/or imaging targets. We envision an early detection/diagnosis platform performed during the recommended annual low-dose computed tomography (LD-CT) lung cancer screenings for heavy smokers. However, LD-CT and all current imaging modalities are not suitable for SCLC early detection even in smoking enriched populations due to lower than required sensitivity/specificity and risk/benefit analyses. Here, we propose a two-tiered approach, with a blood test that detects the presence of AAb specific for SCLC that would trigger immuno-positron emission tomography (immunoPET) imaging utilizing a radioimmunoconjugate that specifically targets the autoantigenic proteins expressed only on SCLC tumors. The blood test ensures that only high-risk individuals are screened and the immunoPET confirms and localizes the tumor for future treatment. Thus, in Aim 1, we propose to define the role of SCLC-specific autoantigens (AAg), isolate human B cells specific to the AAg, test the AAg as highly sensitive and specific early detection biomarkers, and sequence the AAb variable regions and clone them into expression vectors to produce human monoclonal recombinant antibodies for imaging purposes. In Aim 2, we propose to perform immunoimaging of SCLC tumors using fluorophore- and radionuclide-labeled AAb immunoconjugates specific for these cancer targeted neoantigens/epitopes. Preliminary data for the 2 antibodies that we have tested so far show that they specifically bind to SCLC tumors in preclinical models, underscoring the feasibility of the entire pipeline. In summary, we will combine AAb-AAg early detection for risk stratification with immunoPET imaging to confirm and localize tumors, thereby establishing an early detection pathway capable of reducing the mortality of this highly aggressive cancer.