Immunomodulation of Localized Lung Adenocarcinoma Prevents Metastases
Abstract
This application directly addresses the following Fiscal Year Lung Cancer Research Program areas of emphasis: (a) Understand the molecular mechanisms of initiation and progression to clinically significant lung cancer. (b) Identify innovative strategies for prevention and treatment of early and/or localized lung cancer. (c) Understand predictive and prognostic markers to identify responders and nonresponders. (d) Understand susceptibility or resistance to treatment. The 5-year survival of early-stage non-small cell lung cancer (NSCLC) patients is 73% for Stage IA, falling to 58% for Stage IB, and 24% for Stage IIIA -- all of which are considered curable. In spite of surgical resection and adjuvant chemotherapy of early-stage NSCLC, lung adenocarcinoma (ADC), and squamous cell carcinoma (SQC), micrometastatic cancer cells that often go undetected and untreated result in recurrence. Among patients with stage IA NSCLC (T1, </=3 cm, as per the eighth edition of the TNM staging manual), following curative-intent resection, 15%-30% will have a recurrence within 5 years. In our investigation of the biological reasons underlying these recurrences, we identified aerogenous invasion of isolated tumor cells away from the main tumor, a new form of invasion, which we termed ?spread through alveoloar spaces (STAS),? as a potential cause associated with higher rates of recurrence and poorer survival. STAS is now a recognized form of invasion in the new 2015 WHO classification of lung ADC. We now have data showing that STAS is present in SQC as well and that STAS+ tumor cells in normal lung and lymph nodes (LNs) are surrounded by a predominance of immunosuppressive cells and a lack of effector cells. We hypothesize that occult metastases in normal tissue, undiagnosed at the time of curative-intent resection of early-stage NSCLC, shape the protumor immunosuppressive microenvironment. Furthermore, we believe that neoadjuvant or adjuvant immunotherapy-induced effector immune responses can infiltrate and modulate the normal tissue immune microenvironment to effector predominance and prevent metastases. In contrast to preclinical metastatic models, the anatomical and pathological investigation of normal lung and LNs harboring occult tumor cells in Aims 1 and 2 provides a clinical model that will help us understand the metastatic tumor cell immunobiology. The emerging promising data from the neoadjuvant checkpoint blockade (CPB) study in resectable NSCLC support the feasibility of our approach of neoadjuvant immunotherapy. By defining the prognostic markers between responders and nonresponders following curativeintent resection of early-stage NSCLC (Aim 1) and by investigating the immune mechanisms underlying the progression of occult metastatic cells to clinically significant metastases (Aim 2), we will be able to develop innovative strategies that use emerging immunotherapies (Aim 3). We propose to administer recently successful checkpoint blockade agents (antibodies that release breaks on immune cells) and administer human T lymphocytes -- which is a type of immune cell -- that are genetically engineered to target tumor antigens by use of a chimeric antigen receptor (CAR). Based on our promising preclinical and clinical data, we will target two specific antigens that play a key role in tumor aggressiveness and are expressed in 80% of lung ADC patient tumors. This approach is predicated on recent successes in adoptive T-cell therapies. The occurrence of complete responses in patients with a large tumor burden underscores the potential of targeted T cells as well as the need to increase their potency in detecting micrometastases by educating them. We will ?educate patient CAR T cells? by using them against their own tumors. Educated T cells will then gain enhanced detection and immunotherapeutic abilities that will allow them to attack and kill micrometastatic tumor cells. Our ultimate goal is to develop a personalize
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710288
Entities
People
- Prasad S Adusumilli
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army