Stage IV

Approximately 25% of the patients diagnosed with non-small cell lung cancer (NSCLC) exhibit early-stage disease. Patients with early-stage (I/II) NSCLC are routinely treated by surgery, which results in local control. However, systemic relapse (metastasis) occurs in 50% patients within 5 years of surgical intervention even with additional therapy such as chemotherapy and/or radiation. Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis have revolutionized the treatment landscape, generating therapeutic efficacy in approximately 25% of patients in early and advanced stages of lung cancer. However, there are currently inconclusive studies as to 1) timing of treatment 2) optimal combination therapy 3) prediction of patient response. In order, to recapitulate early-stage lung cancer treatment and metastatic recurrence, we have established a murine model of resection and recurrence. Our preliminary data has revealed a major immune response at the level of the tumor draining lymph node (TDLN) with PD-1 checkpoint blockade. In addition, this response is primarily responsible for T-cell memory differentiation, proliferation, and survival with subsequent decrease in metastatic recurrence in responding mice. Given these results, we hypothesize that optimal therapy against metastatic recurrence will be dependent on establishment of appropriate T-cell memory “immunosurveillance”. In addition, we have shown that the memory nodal response can be augmented by utilizing a cytokine immunomodulatory combination strategy with cure in over 70% of mice. Importantly, we have characterized that these specific T-cell memory population are uniquely found in the TDLN of early-stage patients (i.e. not in the primary tumor or peripheral blood that is commonly interrogated). In this proposal we will utilize a combination of both novel preclinical mouse models and patient-derived tumor draining lymph node T cells, to dissect molecular and cellular mechanisms of “immune-memory” response or resistance to immunotherapy, the key steps in establishing immunosurveillance for freedom from metastatic recurrence.

Social circumstances in which we are born and live are some of the most important factors influencing our health. For people with cancer, these social circumstances (social determinants of health) drive differences in access to cancer screening and diagnostic tests, stage at diagnosis, and the types of treatments they are offered and receive. The treatment options for people living with lung cancer have changed drastically over the last decade with the addition of immunotherapies and targeted drugs. However, these treatments are not accessible to all. The high costs of cancer treatments and time lost from work make people with cancer more vulnerable to financial hardship, that could affect their ability to receive cancer treatments. In this study, we hope to understand how social needs (e.g., food access, ability to pay bills, access to transportation, housing stability, social isolation, and loneliness) relate to the use of healthcare, quality of care patients with lung cancer receive, and quality of life during their treatment. To do this, we will survey 150 patients with unresectable lung cancer within one month of start of systemic treatment and at 3 and 6-months during their treatment. We will measure how social needs change over time and relate to the use of healthcare for acute problems (i.e., emergency room visits, admissions to the hospital, and urgent care visits), quality of life, and quality of care received. To obtain an in-depth understanding of how social needs can affect patient care, we will interview 30 oncology providers. Providers will be asked if and how they consider the social needs of their patients when making treatment and clinical decisions. This study will give us essential information on how to better support patients with lung cancer who face social needs that impact their daily lives and cancer care.

The number of lung cancer cases in young patients (<50 years of age) is increasing across the globe, from Asia to the United States. Young patients with lung cancer are more likely to be women, of Hispanic or Asian descent and be diagnosed with metastatic disease. In this patient population, a lung cancer diagnosis is not age normative and is profoundly disruptive. Young patients often receive more aggressive treatments and face long-term side effects. While we have seen substantial progress in mental health research in recent years, little is known about the psychological needs of young patients with lung cancer, including how they compare to those of older patients, the financial toxicity associated with their cancer treatments, and how their experiences with the healthcare system impact their wellbeing. Most survivorship studies in lung cancer have included small numbers of young patients with lung cancer, with many of these studies preceding newer cancer treatments like targeted therapy and immunotherapy.

We proposed a mixed-method study that will be designed in conjunction with an experienced research team and lung cancer patient advocates. The study will be divided into two phases 1) we plan to administer a survey that explores the psychosocial needs and the financial impact of cancer treatments to a group of young and old patients with lung cancer; this survey could be completed online, in person, or over the phone with trained personnel 2) following the survey completion, information from the survey will be used to create a guide for focus group discussions; we will conduct four focus groups with young patients with lung cancer to expand on the knowledge obtained from the survey. Focus groups are a powerful way to gain a comprehensive understanding of patient experiences by interacting on a personal, exploratory level to hear patient voices and understand their needs. We will also investigate the differences in these needs by gender and race/ethnicity in our two groups. The study results will be shared with the lung cancer patient community via a series of webinars.

The knowledge obtained from this study will be used to create the first clinical program dedicated to young patients with lung cancer in the nation and the creation of an international consortium that will focus on understanding why the number of lung cancer cases is increasing in patients <50 years of age. Most importantly, we will use the information to create interventions to improve this vulnerable population's clinical care and psychosocial support. Our study will be the first of its kind to critically evaluate the psychosocial needs of young patients with lung cancer in a diverse patient population with a secondary focus on their experiences with the healthcare system and the financial impact of a cancer diagnosis and treatments.

Radiation therapy has become a staple of cancer treatment because it provides a method for producing lethal damage in cancer cells while sparing nearby healthy tissues. Only more recently has it been shown that radiation may also control the growth of satellite tumors–tumors far from the radiation target. This capacity of radiation to affect tumors indirectly is called the abscopal effect and appears to occur because radiation of a small target area stimulates an immune system response throughout the entire body. The demonstration that radiation therapy can augment the body’s natural immune defenses in this way, producing regression of non-irradiated tumors, has led to a radical rethinking of the therapeutic uses of radiation. Thus, contemporary treatment strategies in radiation oncology are based not only on the capacity of radiation to kill cells directly but rely also on remote immune-mediated effects to destroy cancers that have spread. One of the most promising of such strategies involves a combination of radiation therapy and drugs that stimulate the immune system (immunotherapy). In our laboratory, we have tested such a regimen in a mouse model of disseminated lung cancer and have shown that high-dose radiation therapy delivered to select tumors in combination with two immunotherapy agents can significantly inhibit the growth of satellite tumors. We would now like to extend our results with immunotherapy and high-dose radiation by developing a protocol that further exploits the ability of radiation to work in synergy with our natural immune responses. Several research groups have reported favorable results combining immunotherapy both with high-dose radiation and with low-dose radiation delivered to other secondary tumors. Preliminary evidence, however, suggests that low-dose radiation may actually do more to enhance natural immune defenses if it is given in the form of repeated very low dose pulses. The present study will thus employ an animal model of disseminated lung cancer to test a new radiation protocol with possibly enhanced immune effects. The results will determine if the therapeutic efficacy of immunotherapy in combination with high-dose and low-dose radiation can be improved by the use of low-dose radiation given to satellite tumors in the form of repeated very low-dose pulses.