Stage IV

RET or rearranged during transfection

Read more about Novel Protein Degraders for Treating RET Positive Cancer

Developing new therapeutic approaches for RET-positive cancers

2024

Partner Awards

Grant title (if any)

The Hamoui Foundation/LUNGevity Lung Cancer Research Award Program

Romel Somwar, PhD

Memorial Sloan Kettering Cancer Center

New York

This project aims to develop new therapeutic approaches for RET-positive cancers, focusing on overcoming resistance to currently available RET inhibitors. Dr. Somwar and colleagues will investigate ways to block the growth of lung cancers with altered RET in a pathway called MAPK (mitogen activated kinase), which is involved in many biological processes involving cell growth and survival. MAPK is implicated in developing resistance to RET inhibitors and finding strategies to target this pathway in combination with RET could benefit many patients who have no approved therapy options after tumor reoccurence.

Research Summary

Lung cancers are one of the leading causes of death in the US. Significant progress has been made over the past three decades to understand the biology of lung cancers and to stratify these diseases into subsets of patients who will get the maximum benefit of a given form of therapy. New technologies now allow for each patient to have their tumor DNA sequenced to find genetic causes of their cancer. Many genes that regulate cell growth are altered by mutations that cause the unrestricted growth that lead to cancer. Scientists have developed strategies to take advantage of these aberrant genes by finding chemicals or biological agents that will antagonize the protein products of these genes. One gene that is altered in 2% of lung cancers is called RET and there are two drugs that block the tumorigenic function of this cancer-causing gene (oncogene). Although patients respond very well to these two anti-RET drugs at first, they soon become resistant to the therapeutic effects. Additional genetic changes in RET or other genes in the cancer cells that regulate growth are responsible for the drug resistance. Our goal in this grant proposal is to find ways to block the growth of lung cancers with altered RET that stopped responding to anti-RET inhibitors. The strategy that we will test involves the simultaneous inhibition of RET and other proteins in another growth promoting pathway called the MAPK (mitogen activated kinase) pathway. We believe that this therapeutic strategy can benefit more than 30% of patients who stop responding to current drugs that target lung cancers with RET genetic alterations.

Technical Abstract

RET fusions result from abnormal rearrangements of the kinase domain of RET with other non-essential genes and drive tumorigenesis. These oncogenic chimeric tyrosine kinases are found in approximately 2% of non-small cell lung cancer (NSCLC).Two FDA-approved selective RET inhibitors (selpercatinib and pralsetinib) have shown great response rates in lung cancer patients. However, resistance to RET inhibitors inevitably occurs, limiting therapeutic benefit. Multiple mechanisms of resistance to RET inhibitors have been described, including acquired RET solvent front mutations (G810R/S/C/V), and RET-independent mechanisms of resistance due to amplifications of other receptor tyrosine kinases (RTK) including MET, FGFR1 and ERBB2, and alterations in the RAS-MAPK pathway. Some second-generation RET inhibitors that target secondary RET mutations have been recently developed including vepafestinib (TAS0953/HM06) which is currently being tested in phase I/II clinical trials in the US and Japan for RET fusion positive lung cancer. There is a clinical need to identify mechanisms of resistance to vepafestinib and develop strategies to overcome them.

RET with solvent front mutations, amplification of MET/FGFR1/ERBB2 and RAS-MAPK pathway mutations account for >30% of all resistance mechanisms to first-generation RET drugs, and importantly, all of these alterations are expected to activate the RASMAPK pathway. Therefore, a therapeutic strategy that tackles RAS-MAPK pathway activation is expected to benefit >30% of patients who acquire resistance to first-generation RET drugs. Moreover, given that RET fusions, like all tumors arising from activated RTKs engage the RAS-MPAK pathway for oncogenesis, we believe that many treatment-naïve patients may also benefit from a therapeutic strategy that targets RET and the RAS-MAPK pathway.

Our first goal in this proposal is to simultaneously address resistance due to RAS-MAPK pathway alterations and extending the benefit of first-generation RET drugs by developing a combination therapy strategy involving RET and pan-RAS, MEK1/2 or ERK1/2 inhibitors. Our second goal is to decipher mechanisms by which the transcription factor capicua (CIC) regulate RET-driven tumorigenesis and resistance to RET inhibitors. We will perform transcriptomic, epigenic and proteomic profiling to gain insights into RET-ERK-CIC interaction. Our third goal is to identify and target resistance mechanisms to vepafestinib, so that a therapeutic strategy will be in place for when patients being treated with this drug develop resistance.

Our team includes leaders in the field of lung cancer clinical and translation research who have been at the forefront of lung cancer genomics and therapy, developing state of the art therapeutic strategies. We are well positioned to translate the findings from this study to the clinic within two years. These studies have the potential to benefit more than 30% of lung cancer patients with RET fusions.

Key words

RET or rearranged during transfection

Tyrosine kinase inhibitors (TKIs)

Read more about Developing new therapeutic approaches for RET-positive cancers

Immunogenic peptide priming of dendritic cells for RET+ NSCLC

2024

Partner Awards

Grant title (if any)

The Hamoui Foundation/LUNGevity Lung Cancer Research Award Program

Amy Cummings, MD, PhD

University of California, Los Angeles

Los Angeles

This project will explore the use of neoantigens to evaluate immunogenic priming of dendritic cells (DC) in RET+ NSCLC. Neoantigens are short protein fragments present only in cancer cells that bind to genetically encoded proteins known as human leukocyte antigens (HLA). Dr. Cummings will use features of HLA to predict which cancer-specific protein fragments best match an individual’s immune system, utilizing a biobank of RET-rearranged NSCLC biospecimens. This approach could help identify optimal immunogenic targets, that could be translated into a pathway for clinical use of personalized DC vaccines.

Research Summary

RET-rearranged non-small cell lung cancer (NSCLC) is a rare subtype of lung cancer that is driven by growth signals triggered by RET activation. RET-specific inhibitors are effective initially, but most benefit from this treatment for only 1-2 years before additional treatment is needed. Chemotherapy is a widely-available option but typically provides less than six months of benefit, and it is unclear whether immunotherapy alone or in combination with chemotherapy is a better option. Findings from other gene-rearranged NSCLC studies, particularly those on ALK-rearranged NSCLC, suggest that immunotherapy works better when the immune system is better exposed to abnormalities created by the gene-rearrangement. These are neoantigens, or short protein fragments present only in cancer cells that bind to human leukocyte antigen (HLA), a scaffold that displays these protein fragments to the immune system. One issue with this approach is that these fragments have to be specifically matched to the immune system of an individual, and even the most common forms of HLA are only found in 20% of people. This means that these types of approaches would be applicable to at most 1 out of 5 people with RET-rearranged NSCLC. Our techniques broaden this approach by using features of HLA to predict which cancer-specific protein fragments best match an individual’s immune system (motif neoepitopes), including neoantigens from RET rearrangements and those predicted from the individual’s tumor. We propose to use our biobank of RET-rearranged NSCLC biospecimens, which have not been previously analyzed, to determine whether we can detect and elicit enhanced immune responses with motif neoepitopes, neoantigens related to RET-rearrangements, or other predicted neoantigens. We can then offer this approach in a currently open clinical trial investigating immune system optimization through an application to the FDA.

Technical Abstract

RET-rearranged non-small cell lung cancer (NSCLC) presents challenges in management following progression on selective tyrosine kinase inhibitors (TKIs). Platinum-based chemotherapy and docetaxel are available options but are without durable benefit. Real world data with single-agent and combination chemo-immunotherapy suggests modest benefit and possible efficacy if immunotherapy-based approaches are appropriately optimized. For the past decade, our group has meticulously curated hundreds of NSCLC biospecimens including matched tissue and blood from multiple timepoints, including 7 RET-rearranged NSCLC cases that have not previously been analyzed. We have extensive expertise in neoepitope prediction and personalized immunotherapy through dendritic cell (DC)-based vaccination. Our most recent collaboration enabled functional assessments of T-cells through nanovial-based affinity repertoires, further enhancing our ability to predict and translate immunogenic peptides through a personalized vaccine-based program. We propose to use our RET-rearranged NSCLC biospecimens to systematically study T-cell-specific responses to identify optimal immunogenic peptide targets, an approach that could be translated in our currently open and approved DC vaccination trial (NCT03546361) through single patient exemptions.

Key words

RET or rearranged during transfection

Read more about Immunogenic peptide priming of dendritic cells for RET+ NSCLC

Targeting tumor associated macrophages in immunotherapy resistant NSCLC

2024

Partner Awards

Grant title (if any)

Brown/LUNGevity Award to Understand Mechanisms of Resistance to Immunotherapy

Dwight Owen, MD, MSc

The Ohio State University

Columbus

This project will investigate the role of cells called macrophages, key components of the immune system that have multiple functions, including immune surveillance within a unique communication pathway called hedgehog (Hh). The hedgehog signaling pathway is involved in cell growth and differentiation, as well as maintenance of stem cells and tissue repair. Disruption or inhibition of Hh can create an environment that is less favorable for survival of cancer cells, allowing a patient’s immune system to combat it more effectively. This research has the potential to benefit patients who have been diagnosed with NSCLC, who have not responded to current treatments including immunotherapy by boosting the body’s own defense mechanisms.

Research Summary

Lung cancer remains one of the most lethal types of cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for a majority of cases. The goal of our research is to better understand the relationship between certain immune cells called macrophages and NSCLC, and how this interaction contributes to the cancer's survival and resistance to treatment. The scientific premise of our project lies in investigating a unique communication pathway known as hedgehog signaling within these macrophages and determining how it impacts the immune system's ability to fight lung cancer. If successful, our research has the potential to benefit patients who have been diagnosed with NSCLC, particularly those who have not responded to current treatments including treatment with immune therapies. By disrupting the hedgehog signaling pathway in macrophages, we hope to create a tumor immune environment that is less favorable for cancer cell survival, allowing patients' immune systems to effectively combat the disease. This research can pave the way for innovative therapeutic approaches that boost the body's own defense mechanisms.

Technical Abstract

The prognosis for patients with metastatic non-small cell lung cancer (NSCLC) remains poor despite recent progress in immune checkpoint blockade (ICB) therapy. Thus, there is an urgent need to understand mechanisms for lung cancer immune evasion within the tumor microenvironment (TME) in order to develop more effective and durable strategies for treating lung cancer. Tumor associated macrophages (TAMs), a major component of the tumor stromal mass, generally display an anti-inflammatory phenotype and can facilitate tumor growth by promoting angiogenesis, invasion, and metastasis, as well as immune evasion. However, it remains largely undefined exactly how these TAMs regulate anti-tumor immune responses within the TME. Will test the hypothesis that hedgehog signaling in TAMs interferes with recruitment of CD8+ T cells to the TME through the following specific aims: 1) Investigate the role of Hh inhibition with anti-PD-L1 therapy in non-small cell lung cancer; 2) Study the impact of Hh inhibition on TAMs and changes within the TME. The objective of this project is to understand signals required for functional polarization of TAMs within the TME and its contributions to immune cell dysregulation and cancer progression, and whether combined Hh inhibition and ICB can overcome resistance to immunotherapy.

Key words

Immune checkpoint inhibitors

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Developing EGFRxHER3 bispecific CAR-T cells for targeting EGFR TKI DTPCs

2024

Career Development Award

Yan Yang, PhD

MD Anderson Cancer Center

Houston

In patients with EGFR-mutant NSCLC, tyrosine kinase inhibitors (TKIs) have been an effective treatment, but over time these patients develop resistance to TKIs, leading to tumor relapse. Dr. Yang’s project focuses on cancer cells called drug-tolerant persisters (DTPs), which are implicated in TKI resistance. A gene called HER3 is expressed in DTPs, and Dr. Yang will use specially engineered immune cells, called CAR-T cells, to target both HER3 and EGFR simultaneously. If successful, this approach would result in a bi-specific CAR-T cell that can be further evaluated in clinical trials.

Research Summary

In lung cancer patients with a specific genetic mutation in EGFR, certain drugs can be helpful, but over time, the cancer can learn to resist these drugs, making them less effective. We're focusing on a small group of tough cancer cells, called DTPCs, that survive the initial treatment because they might be the key to curing the cancer for good. We've noticed that a gene called HER3 is expressed more in these cells. We also have promising results from CAR-T cell therapy. It is a treatment using T cells, a type of immune cells, engineered with the chimeric antigen receptor (CAR) so they can find and destroy cancer cells. We've found that CAR-T cells targeting EGFR can kill DTPCs. We believe if we use these T cells to attack both HER3 and EGFR at the same time, we might have a better chance of killing off these stubborn cancer cells. To make sure this idea works, we'll first check if HER3 is indeed more expressed in these DTPCs in the lab and samples from patients. Then, we'll test our HER3-targeting CAR-T cells to see if they can kill these DTPCs. If that looks promising, we'll tweak the T cells to target both HER3 and EGFR and see if they work even better. If all goes well, we'll be able to make one of the first effective CAR-T cells to target both HER3 and EGFR and try them out in clinical trials.

Technical Abstract

In NSCLC patients harboring mutant EGFR, treatment with tyrosine kinase inhibitors (TKIs) has demonstrated efficacy. However, the emergence of resistance to EGFR TKIs remains a significant challenge, leading to disease progression. Targeting drug-tolerant persister cells (DTPCs), a rare subpopulation surviving initial treatment, emerges as a more effective strategy than awaiting the development of complete drug resistance, holding potential for curative cancer therapy. Based on our preliminary data on the upregulation of HER3 in DTPCs resistant to EGFR TKIs and the potent antitumor activity of EGFR-targeting chimeric antigen receptor (CAR)-T cells against DTPCs. We propose that HER3 is a promising target expressed on EGFR-TKI DTPCs and that CAR-T cells simultaneously targeting both EGFR and HER3 are an effective approach for targeting DTPCs with improved overall efficacy. In this proposal, we will evaluate HER3 as a therapeutic target for CAR-T cell therapy against EGFR-TKI DTPCs by validating its expression in DTPCs using in vitro cell models, in vivo xenograft and PDX models, and patient tissues. Additionally, we will evaluate the anti-tumor activity of HER3-targeting CAR-T cells against DTPCs. Subsequently, we will develop and characterize EGFRxHER3 bispecific CAR-T cells, evaluating their CAR expression, antigen binding affinity, and anti-tumor activity. We next will assess their anti-tumor efficacy in xenograft and PDX models to guide the selection of the most promising bispecific CAR-T cells for further development. If completed successfully, we will have EGFRxHER3 bispecific CAR-T cells ready for GMP-compliant clinical-grade CAR manufacturing, in preparation for clinical trial evaluation.

Key words

Epidermal growth factor receptor (EGFR)

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Building Reliable Oncology Navigation to Ensure Adjuvant Management: BRONx-TEAM Project

2024

Career Development Award

Tamar Nobel, MD, MPH

Montefiore Medical Center

Bronx

The introduction of targeted therapies and immunotherapy for early-stage lung cancer is associated with improved survival, but patients can only benefit if they partake in adjuvant and neoadjuvant therapies. Data has shown that inequalities exist for patients with lower socioeconomic status as well as non-White patients when it comes to being referred for and receiving treatment after surgery. These inequalities are likely to increase as new drugs are developed in clinical trials comprised of predominantly white patients. In this project, Dr. Nobel will study the impact of disparities on uptake of adjuvant therapy for NSCLC in a largely minority patient population at Montefiore Medical Center in Bronx, NY. She will provide social support and health literacy to engage patients in their care and collect genetic data about their tumors, which will contribute to future clinical trials that are more inclusive.

Research Summary

Systemic therapy after surgery to remove lung cancer has been demonstrated to improve survival. However, data has shown that there are inequalities in which patients are referred for and receive treatment after surgery, specifically for lower socioeconomic status and non-White patients. As new treatments have been developed, these inequalities are likely to increase as these drugs have been developed in clinical trials predominantly composed of White patients and the benefits in other populations are not known. We have previously demonstrated that using nursing and peer navigators to help guide patients in their cancer care improves treatment adherence in our predominantly Black and Hispanic low socioeconomic status population in the Bronx. The BRONx-TEAM project aims to improve patient outcomes by using a navigation pathway focused on increasing patient adherence to systemic therapy after surgery for non-small cell lung cancer resection. We believe that by providing social support and improving health literacy we can get patients to be more informed and engaged in their cancer care. Furthermore, we will gather genetic data about the patients tumors. Given our patient population, we have a unique opportunity to contribute to the literature to understand the relationships between tumor genetics, treatment types and outcomes in non-White patients. Furthermore, we will investigate the use of a commercial genetic panel to assess risk for recurrence. Given the lack of this type of data in low income non-White patients, we believe that this exploratory portion of our study will serve as an important foundation for future clinical trials that are more inclusive than the currently available literature.

Technical Abstract

As seen in the phase III trial CheckMate 816 (CM816), neoadjuvant anti-PD-1+chemotherapy improves survival for patients with resectable non-small cell lung cancer (NSCLC), with pathologic response as a major trial endpoint. Our team led the Central Pathology Review for CM816, and we showed the first prospective evidence that the full spectrum of % residual viable tumor (%RVT) associates with event free survival. Given the data supporting pathologic response as a survival surrogate, %RVT will likely be incorporated into the next generation of clinical trials and may ultimately guide clinical decision-making. %RVT is primarily evaluated using visual assessment of routine hematoxylin and eosin-stained slides. We developed a machine learning-based approach to score %RVT, which allows for a standardized approach that can be completed rapidly for a large volume of patients, and we propose to test this algorithm in resection specimens from CM816. Additionally, we will use multiplex immunofluorescence (mIF) to quantify individual features of pathologic response, locate them within the larger tumor bed, and determine the relative contribution in predicting patient outcomes. Furthermore, we will use the novel AstroPath platform, a mIF whole-slide imaging platform that uses algorithms first developed in astronomy to generate tumor-immune maps, to identify additional pre- and on-treatment biomarkers of response. Our goal is to leverage emerging technologies (i.e, machine learning and mIF) to develop the next generation of pathology biomarkers, including pathologic response assessment, and to identify additional features that can potentially be targeted in combination with anti-PD-(L)1+chemotherapy to improve clinical benefit in patients with NSCLC.

Key words

Biomarker or biomarker testing

Adjuvant or neoadjuvant

Immune checkpoint inhibitors

Molecular profile or molecular testing

Read more about Building Reliable Oncology Navigation to Ensure Adjuvant Management: BRONx-TEAM Project

Next-generation pathologic response assessment in patients with lung cancer

2024

Career Development Award

Julie Deutsch, MD

Johns Hopkins School of Medicine

Baltimore

Dr. Deutsch’s proposal centers around finding better pathologic predictors of response to neoadjuvant IO in early stage NSCLC. She will utilize machine learning/artificial intelligence to test an algorithm that she and her team have developed that assesses percent residual viable tumor (%RVT), which is the amount of tumor left at the time of surgery. Dr. Deutsch will also characterize tissue specimens using a novel immunofluorescence platform to identify cell types and spatial relationships that are associated with patient benefit to immunotherapy+chemotherapy. This approach can help inform which patients should receive a given therapy, how they will respond, and additional possible targets for the development of new therapies.

Research Summary

Immunotherapy revolutionized the treatment of lung cancer, and is now being extended so patients can receive therapy before surgery. This was supported by a large clinical trial, CheckMate 816 (CM816), where patients with lung cancer showed improved survival when treated with immunotherapy+chemotherapy before surgery, compared to chemotherapy alone followed by surgery. However, there is an unmet need to identify who is most likely to benefit from such an approach. To address this gap, we will apply novel, next-generation pathology biomarkers utilizing machine learning/artificial intelligence and multispectral imaging. Specifically, we have shown that the amount of tumor left at the time of surgery, termed percent residual viable tumor (%RVT), predicts survival. To date, %RVT assessment is primarily performed visually on glass slides using a light microscope. We developed a machine learning-based algorithm for assessing %RVT on digitized glass slides using a small cohort of patients at Johns Hopkins to improve standardization and throughput in preparation for broad usage. Here, we will test the algorithm’s performance in a larger cohort of patients (the CM816 patients). Additionally, we will characterize tissue specimens using the novel multiplex immunofluorescence AstroPath platform, which uses algorithms first developed in astronomy, to identify cell types and spatial relationships that are associated with patient benefit to immunotherapy+chemotherapy. Our goal is to use cutting-edge technologies to improve the care of lung cancer patients by informing which patients should receive a given therapy, how well patients will do after receiving therapy, and possible additional targets for the development of new therapies.

Technical Abstract

Key words

Biomarker or biomarker testing

Adjuvant or neoadjuvant

Immune checkpoint inhibitors

Molecular profile or molecular testing

Read more about Next-generation pathologic response assessment in patients with lung cancer

Eliminating Drug-Tolerant Persister Cells Through T-cell Engineering

2023

Partner Awards

Grant title (if any)

EGFR Resisters/LUNGevity Lung Cancer Research Award

Alexandre Reuben, PhD

University of Texas MD Anderson Cancer Center

Houston

In this project, Dr. Reuben and colleagues aim to develop a novel therapeutic strategy harnessing immune response in EGFR-mutant NSCLC. He will use engineered T cells with receptors targeting EGFR antigens to eradicate drug-tolerant persister (DTP) cells, preventing the emergence of resistance following treatment by osimertinib. This work lays the foundation for use of TCR-engineered T cells in treating patients with EGFR mutations.

Research Summary

Although targeted therapies are extremely effective in destroying tumors, they inevitably leave behind a few cancer cells which persist. These are the cells which eventually become resistant to therapy and lead to the death of patients. Although checkpoint blockade immunotherapy has been largely unsuccessful in EGFR-mutant tumors, immunotherapy via cell therapy may offer promise in this setting. EGFR mutations can give rise to short peptides at the surface of tumor cells, called antigens, which allow the immune system to distinguish tumors from their normal counterparts and to specifically destroy them. Importantly, we have identified several antigens that are found solely on or enriched within EGFR-mutant tumors persisting following treatment with EGFR targeted therapies such as osimertinib/Tagrisso. As a result, we have developed a library of receptors which can be engineered into immune cells to allow their direct recognition and destruction of persisting EGFR-mutant cancer cells on the basis of the unique antigens they display. Here, we propose to test a novel approach to eradicate these EGFR-mutant drug persister cells by treating them with engineered immune cells to eliminate the last remaining persister cell and prevent the emergence of resistance following exposure to osimertinib. Our proposal includes two aims: Aim 1 will focus on determining the impact of EGFR-mutant persister cells on the function of immune cells and on their ability to recognize and kill tumor cells. Aim 2 will focus on assessing the ability of receptor- engineered immune cells to eliminate EGFR persister cells when combined with EGFR targeted therapy in vitro and in vivo.
Together, these aims will allow us to determine the therapeutic potential of this novel treatment strategy approach. Our proposal is highly translational, as we have entered into a partnership with Alaunos Therapeutics, a cellular therapy company performing a clinical trial using engineered immune cells at MD Anderson which could facilitate our ability to move these findings into the clinic. Due to the prevalence of the antigens we are targeting (one of which is found in ~90% of lung cancer patients), our approach could extend to almost all patients harboring EGFR mutations.

Technical Abstract

EGFR mutations render lung cancer tumors resistant to immunotherapy via checkpoint blockade. Fortunately, the development of EGFR tyrosine kinase inhibitors (EGFRi) such as Osimertinib has provided impressive clinical responses in a majority of patients. However, many of these patients eventually recur. Studies by our group and others have identified some of the mechanisms associated with resistance to EGFRi. Although EGFRi eliminate the overwhelming proportion of tumor cells, a limited number of cells persist and have thus been termed DTPCs (drug-tolerant persister cells). Importantly, it is these DTPCs which eventually become resistant and are to blame for patient recurrence, highlighting the importance of eradicating these cells before they become fully resistant. Resistance to EGFR TKIs can emerge via two main mechanisms: oncogene-dependent and independent. While oncogene-dependent mechanisms include accumulation of additional mutations in EGFR such as T790M and C797S, oncogene-independent mechanisms include epithelial to mesenchymal transition (EMT) and small cell transformation. Despite their lack of responsiveness to EGFRi at this juncture, each of these mechanisms offers a unique opportunity to leverage cellular immunotherapy to eradicate EGFR mutant DTPCs before they become resistant, thereby improving clinical outcomes. Over the last few years, we have built a library of T cell receptors (TCRs) which confer the ability to recognize epitopes derived from common EGFR mutations including L858R, T790M, and C797S, as well as from the tumor-associated antigen (TAA) FOXM1 which is overexpressed in tumors, and upregulated upon resistance to EGFRi through EMT and small cell transformation. Therefore, we hypothesize that engineering T cells with receptors targeting these EGFR- and FOXM1-derived antigens allows the destruction of DTPCs following treatment with EGFRi, thereby preventing the emergence of resistance. We propose the following specific aims: Aim 1. Assess the impact of drug-tolerant persister cells on CD8 T cell phenotype and function. In this aim, we will identify immune suppressive mechanisms deployed by DTPCs to inhibit T cell response and function. Aim 2. Evaluate the potential of T cell engineering to eliminate DTPCs. In this aim, we will test the ability of TCR-engineered T cells recognizing epitopes derived from EGFR(L858R) and EGFR(T790M) and from the FOXM1 TAA to eradicate DTPCs in vitro and in vivo. Overall, our proposal aims to demonstrate for the first time that TCR engineering can be used in combination with EGFRi to eradicate EGFR-mutant DTPCs. As a result, this work lays the foundation for use of TCR-engineered T cells in this treatment setting. Most importantly, MD Anderson is currently running a clinical trial employing TCR engineering for the treatment of lung cancer with Alaunos Therapeutics which could provide a clear pathway towards the clinic.

Key words

Acquired resistance

Epidermal growth factor receptor (EGFR)

Targeted therapy

Read more about Eliminating Drug-Tolerant Persister Cells Through T-cell Engineering

Targeting CD74 to Overcome Resistance to EGFR Inhibitors in Lung Cancer

2023

Partner Awards

Grant title (if any)

EGFR Resisters/LUNGevity Lung Cancer Research Award

Susumu Kobayashi, MD, PhD

Beth Israel Deaconess Medical Center

Boston

Tyrosine kinase inhibitors (TKI) are a class of drugs that are used to treat EGFR NSCLC. These drugs eventually stop working and some cancer cells called drug-tolerant persisters (DTPs) are implicated in this resistance. Dr. Kobayashi and his team have found that a protein called CD74 plays a role in developing a resistance to osimertinib. In this project, he will investigate whether CD74-expressing cells allow for the development of DTPs and if inhibition of CD74 by combining an antibody-drug conjugate (CD74-MMAE) with osimertinib, prevents resistance. If successful, this has the potential to significantly impact the survival of EGFR patients by allowing them to stay on osimertinib for a longer duration.

Research Summary

Non-small cell lung cancer (NSCLC) with certain mutations in the EGFR gene at advanced stages can be treated with drugs called EGFR tyrosine kinase inhibitors (TKIs). However, these drugs can eventually stop working as cancer cells develop resistance. Recent evidence suggests that some cancer cells called drug-tolerant persisters (DTPs) are responsible for this resistance. These cells survive and adapt to TKIs during early phases of therapy, and can give rise to resistant cells through various mechanisms. Therefore, targeting DTPs may be a way to prevent resistance to EGFR TKIs. Our research team has found that a protein called CD74 plays a critical role in the drug-tolerant state of cancer cells. We have found that CD74 upregulation signals resistance to a third-generation EGFR TKI called osimertinib, and blocks apoptosis, which allows tumors to grow back. Based on these findings, we hypothesize that elimination of CD74-expressing cells in addition to EGFR inhibition may be a better treatment strategy than EGFR inhibition alone, because it could suppress the emergence of DTPs. In our proposed research, we will investigate whether CD74-expressing cells give rise to DTPs, and how CD74 is upregulated and prevents apoptosis in tumor cells exposed to osimertinib. We will also evaluate the effectiveness of CD74-antibody-drug conjugates (ADCs) alone or in combination with EGFR TKIs using cell culture systems and animal models. CD74-ADCs target and eliminate tumor cells expressing CD74 on the cell surface. Our goal is to better understand the mechanisms underlying resistance to EGFR-TKIs and the emergence of DTPs, and provide preclinical evidence that combined inhibition of CD74 and EGFR is a rational and effective treatment strategy for EGFR-mutated lung cancer.

Technical Abstract

The development of tyrosine kinase inhibitors (TKIs) revolutionized treatment of advanced/metastatic non-small-cell lung cancer with EGFR mutations. Osimertinib is one of several third-generation EGFR TKIs and shows improvement in progression-free survival and overall survival compared to first- and second-generation EGFR TKIs. However, intrinsic or acquired resistance to osimertinib emerges in essentially all patients, which prevents a cure for EGFR-mutated lung cancer. Therefore, it is necessary to develop better strategies to improve clinical outcomes. Recent evidence suggests that drug-tolerant persister (DTP) populations of cancer cells, which survive and adapt to TKIs during early phases of therapy, play an important role in the emergence of resistance to targeted therapies. Such DTP cells give rise to resistant cells via diverse mechanisms and contribute to spatial and temporal heterogeneity of tumors. Therefore, targeting DTP cells may be an efficient strategy to prevent resistance to EGFR TKIs. Using lung cancer cell line models and clinical specimens, we recently identified CD74 as a novel gene that plays a critical role in the drug-tolerant state. In vitro and in vivo experiments demonstrate that CD74 upregulation signals osimertinib resistance and blocks apoptosis, enabling tumor regrowth. Based on preliminary evidence, we hypothesize that CD74 increases tumor cell survival in the presence of TKIs and that elimination of CD74 positive cells by CD74-antibody-drug conjugates (ADCs) may suppress the emergence of DTP cells, which underlie relapse. In this proposal, we will test this hypothesis by: 1) confirming that CD74-positive cells are tolerant to EGFR TKIs; 2) investigating the mechanisms by which osimertinib induces CD74 expression; and 3) evaluating a combination of CD74-ADCs and osimertinib to prevent the emergence of acquired resistance. We will address these questions using cell culture systems and animal models. These experiments should unveil the mechanisms underlying resistance to EGFR-TKIs and the emergence of DTP cells, and provide preclinical evidence that a combination of CD74-ADC and EGFR TKIs is a rational and efficacious treatment strategy for EGFR-mutated lung cancer.

Key words

Acquired resistance

Epidermal growth factor receptor (EGFR)

Biomarker or biomarker testing

Targeted therapy

Read more about Targeting CD74 to Overcome Resistance to EGFR Inhibitors in Lung Cancer

Radiogenomic Biomarker and Multiomic Data Integration to Predict Radiation Response in Lung Cancer

2023

Partner Awards

Grant title (if any)

ASTRO-LUNGevity Residents/Fellows in Radiation Oncology Seed Grant

Funded by the American Society for Radiation Oncology

Kailin Yang, MD, PhD

Cleveland Clinic Foundation

Cleveland

Radiation therapy remains a cornerstone treatment for patients with locally advanced lung cancer, however knowing which patients will respond and which will not respond is still poorly understood. The goal of this project is to analyze genomic and radiomic data from patients with NSCLC to understand how tumors change during therapy and create models to predict therapeutic response that will assist with clinical decision making.

Research Summary

Lung cancer remains the leading cause of cancer death in the USA, and the combination of chemotherapy and radiation remains the mainstay for locally advanced disease. While radiation therapy accounts for nearly half of cancer cures, our understanding of which patients will respond well or poorly remains rudimentary. Medical oncology has seen a flurry of genomic measures and signatures to indicate treatment choice, but in radiation oncology our dosing and combination therapy choices are made empirically, with little, if any, regard to individual patient biology or on-treatment response, with the exception of some geometric changes or clinical gestalt. Our overarching goal in this project is to collect and analyze high temporal density, multi-modality data from lung cancer patients treated with standard of care chemoradiation, with an eye to marrying and correlating our understanding of changing transcriptomics over time to non-invasively observable radiomic feature changes during therapy to outcome. We propose to use modern genomic and radiomic techniques to measure the dynamic responses of non-small cell lung cancer tumors to understand how these tumors change during therapy. Such knowledge will generate broad impact on the precision care for lung cancer patients through developing radiogenomic biomarkers that predict therapeutic response and inform clinical decision making.

Technical Abstract

Radiation therapy is the single most utilized anti-cancer agent; nearly 70% of all cancer patients will receive radiation at some point in their cancer journey. Radiation plays a crucial role in almost half of all cancer cures. The sequencing of the human genome, completed nearly 20 years ago, followed by the large scale cancer sequencing effort in The Cancer Genome Atlas (TCGA) have provided an unprecedented understanding of cancers in the primary and metastatic setting. In those same years, medical oncology has undergone three major phase transitions: targeted therapies have changed the way we think many diseases with specific actionable mutations; immunotherapy has revolutionized the treatment of many of those without; and antibody-drug conjugates have increased the specificity of our cytotoxics. Radiation treatment decision making, however, has not seen these same changes from biological influences, instead having relied on advances in medical physics and computer science to drive our advances. While the number of trials has ballooned in radiation oncology of late, spurred on by encouragement, and funding, from pharmaceutical companies interested in the synergy between novel (and profitable) compounds in the form of immune checkpoint inhibitors and antibody-drug-conjugates, with radiation, our understanding of the relative benefits and best choices for individual patients has not seen the same increases. In fact, we have struggled to parse out the differences between these novel combinations and standard chemoradiotherapy in phase II trials, largely because of the combinatorial nature of our trials, and the sheer number of open questions. In this project, we seek to make headway toward personalizing radiation therapy treatment choices. Leveraging our experience in using gene signatures to predict individual patient radiation benefit, together with expertise in radiomics and genomics, we will track the progress and outcomes of patients with non-small cell lung cancer treated with standard of care chemoradiation using high resolution genomic and radiomic measures. The dynamics of these genomics through time will be correlated to the high temporal density radiomics features to allow for translation and generalization to all patients treated with modern technique. Through these complimentary -omic modalities, we aim to leverage our experience in creating signatures of therapeutic response to admit personalized treatment choice in the upfront setting, and opportunities to change course using real- time information gleaned from daily imaging. This pilot project will enable the development of novel multimodal data integration methodologies to interrogate radiation treatment response in a comprehensive manner.

Key words

Molecular profile or molecular testing

Radiotherapy