Advances in Immunotherapy of Breast and Gynecologic Cancers
The fields of cancer immunology and immunotherapy are making great advances in developing a comprehensive understanding of the mechanisms underlying tumor immune system interactions and the application of this knowledge to the development of effective therapies. One significant obstacle to the widespread use of immunotherapy is that clinical responses vary widely depending on tumor type. This is clearly evident in gynecologic cancers, including of breast, ovary and endometrial origin. This session will focus on how the unique biology of gynecologic cancers has paved the way for exciting developments in immune biomarker development as well as the rational application of immunotherapy.
Advances in Immunotherapy of GI and Pancreatic Cancer
Prior to 2017, there were no approved immunotherapies for patients with gastrointestinal (GI) malignancies. However, as with other diseases, the first four approvals in this area were with PD-1 inhibitors. Pembrolizumab was approved for mismatch repair deficient tumors regardless of tissue of origin and PD-L1+ gastric cancers and nivolumab was approved for mismatch repair deficient colon cancer and hepatocellular carcinoma (HCC). Despite these advances, immunotherapy still has very little practical application to a majority of patients with GI cancers and much more work needs to be done at the basic mechanism level to bring this therapy to more patients with diseases such as pancreatic cancer or to the 80% of patients with HCC that do not respond to single agent therapy.
The pancreatic cancer tumor microenvironment is a formidable fortress against which immunotherapy agents have been marginally effective. These tumors are devoid of cytotoxic T cells partly due to the complex milieu of negative regulators (inhibitory cell populations, cytokines, chemokines, stroma, and metabolites) that exclude anti-tumor immune cells from the tumor. In order to make progress in the development of immunotherapy for pancreatic cancer, basic and translational research efforts are focused on a better understanding of the determinants that contribute to this immune dessert. This session will feature novel preclinical approaches including innovative mouse models to facilitate interrogation of immunotherapy, approaches targeting antagonism of inhibitory cells in the immune microenvironment such as fibroblasts, myeloid-derived suppressor cells, and macrophages, and research manipulating stromal characteristics that typically facilitate tumor growth and immunosuppression in densely fibrotic pancreatic cancers.
While we have experienced some success with HCC, a majority of patients still do not respond to single agent PD-1 inhibition. Similar to pancreatic cancer, the immune microenvironment within liver tumors both primary and metastatic can be immunosuppressive. This is coupled with the complex inflammatory milieu of the hepatic environment which in the context of HCC may be associated with viral infection and furthermore, the liver itself is an immune organ consisting of a complex array of immune cells and local cytokines/chemokines. This unique feature of liver tumors could be exploited for therapeutic benefit if better understood. Research approaches to study liver tumors will be presented.
Advances in Immunotherapy of GU Tumors
The rapid development of immunotherapy in genitourinary tumors over the last several years has led to new standards of care and improved clinical outcomes, with the promise of even greater impact with novel agents and combinations currently in clinical development. However, responses to currently available agents such as checkpoint inhibitors are still low and moreover, varied across bladder, renal and prostate cancers. A deeper understanding of the biology that drives immune exclusion unique to each tumor type will be necessary to identify treatments to enhance the engagement of the immune system to generate a more effective anti-tumor immune response. In this session, expert faculty will review the biological basis for targeting the immune system as cancer therapy in GU cancers, highlight the role for established agents and discuss mechanistic insights to support targeting immune pathways unique to individual tumor types to address treatment resistance to currently established agents.
Advances in Immunotherapy of Hematologic Malignancies
Recent progress in immunotherapy may be the greatest advance in the treatment of both solid and hematological malignancies in decades, though there are still a majority of patients who ultimately succumb to these diseases indicating the urgent need for, still, more progress. Tackling these issues comes with specific opportunities and challenges for patients with hematologic malignancies including leukemias, lymphomas, myeloma, and myeloproliferative neoplasms. Hematologic malignancies distinctions from solid tumors include their derivation, at times, from the same leukocyte subsets being manipulated by immunotherapies as well as their greater expression of antigen-presenting molecules and T-cell co-stimulatory ligands (e.g. MHC-II, and B7 molecules) which might potentiate both CAR and checkpoint therapies. Early CAR-T trials have reported unprecedented efficacy in CD19(+) leukemias/lymphomas and BCMA(+) myeloma and PD1-blockade studies in Hodgkin's, CNS, and NK/T lymphomas have demonstrated amongst the highest response rates of any checkpoint blockade trials. Despite the clinical successes of CAR-T therapies and checkpoint blockade antibodies, not all patients respond and, at the same time, immune-related toxicities can be limiting or lethal for a proportion of patients. Deeper understanding of the predictors and mechanism of these immune-related toxicities will drive improved patient selection, prevention and management.
This session focuses on the clinical efficacy, safety, and mechanistic data of recent trials of cellular and molecular therapies for hematologic malignancies, including CAR-T, CAR-NK, checkpoint inhibitors and other immune modulators. Presentations by physician-scientists will provide an opportunity for attendees to gain an in depth understanding of the state-of-the-art and expected advances over the next decade. As hematologic malignancies have been on the front line of developing novel immunotherapies with amongst the best responses to immune-mediated tumor killing, it is likely that this field will continue to predict advances in solid tumors and advance still greater innovation.
Advances in Immunotherapy of Lung, Head and Neck Cancer
Description coming soon.
Advances in Immunotherapy of Pediatric Malignancies
Immune based approaches have emerged as novel and effective therapies for treatment of cancer. While CAR-T cells have been very effective for therapy of childhood B-ALL, there remains a major need to develop CAR-T cell therapies for treatment of acute myeloid leukemia as well as solid tumors in children. Immune checkpoint inhibitors can lead to durable responses in several adult tumors, however, very little efficacy has been seen in early pediatric trials of these agents. Differences in efficacy of immune based approaches in children and adults likely result from differences in tumor biology (e.g low mutation/neoantigen burden of pediatric cancer), as well as immune fitness (presence of intact thymus and greater naïve immune repertoire in children). Optimal application of the immune based approaches will require specific study of immunity and tumor microenvironment of pediatric tumors.
This session, will focus on unique aspects of pediatric tumors. Speakers will discuss future directions in CART cell therapy for pediatric malignancies beyond their application in B-ALL, studies characterizing immune microenvironments within pediatric tumors and vaccine strategies to boost immunity in children with cancer.
Basic Biology of Tregs
Regulatory T cells (Tregs) have a recognized and critical role in the maintenance of immune homeostasis in mice and man. Tregs are educated in the thymus or generated in the periphery, and then circulate and infiltrate tissues with the goal of fine tuning immunity and counter balancing inflammatory processes to prevent autoimmunity. Despite their critical role in immune homeostasis and maintaining host integrity, their function is known to be hijacked in the context of cancer. The murine and human tumor microenvironment actively recruits Tregs bearing features of activation such as upregulation of the high affinity IL2Ra (CD25) and the immune-regulatory receptor CTLA-4. In mice, prophylactic and therapeutic depletion of Tregs enhances anti-tumor immunity and synergizes with other immune therapies to promote tumor control. In humans, the number of tumor-infiltrating regulatory T cells and their spatial distribution with regards to effector T cells negatively associates with patient outcome underscoring their negative role in anti-tumor immunity and the need for immunotherapies that temper their number and/or function.
In this session, we will discuss the basic biology of Tregs in the context of cancer, our enhanced understanding of their role and function and how this is impacting the development of novel immune therapeutic agents for the treatment of cancer.
Cell-Based Therapies for Solid Tumors
Despite the remarkable achievements over the last five years in cell-based therapies in B-ALL and DLBCL (Hematological Malignancies), the progress and success of these therapeutic approaches in patients with solid tumors has been slow and infrequent. A number of limitations currently exist that are potential mechanism(s) of resistance of cell-based therapies in patients with solid tumors including the lack of defined, antigenic and specific tumor targets, the suboptimal qualities of the T cell product post-transfer (concerning proliferation, trafficking, anti-tumor function and/or persistence) and the tumor microenvironment-mediated resistance including tumor heterogeneity and immunosuppression among others. Multiple approaches are currently under investigation to potentially circumvent some or all of these limitations in cell-based therapies in patients with solid tumors.
This specific session will focus on novel preclinical and clinical therapeutic approaches of cell-based therapies in a variety of pediatric and adult solid tumors. The attendees of the session will have the opportunity to increase their knowledge and understanding in a variety of areas of cell-based immunotherapy including preclinical studies of NK cell therapy of Neuroblastoma and Sarcomas, preclinical and clinical CAR T cell therapy in solid tumors including Glioblastoma, and preclinical and clinical studies of TIL therapy in melanoma and other solid tumors. Methods of circumvention of mechanism(s) of resistance of cell-based therapies in solid tumors will be highlighted throughout the session.
Clinical Management of Cell Therapy Administration
Recent FDA approval of CAR T therapies, combined with advances in tumor-infiltrating lymphocyte (TIL) and other cell based therapies will likely result in widespread use of these modalities both in clinical trials and in standard clinical care. These modalities pose unique clinical challenges, as many practitioners are not familiar with the procedures and potential complications.
In this session we will review common procedures for cell collection and tumor harvesting, cell processing for TIL and CAR T therapy, myeloablation, IL2 administration and common adverse events. Speakers will also review specific potential adverse events seen in prior cell therapy trials, biomarkers and clinical features predictive of adverse events, and biological mechanisms responsible for these adverse events.
Immunomodulatory cytokines can have potent anti-tumor activity, but also often suffer from significant toxic side effects. This session will cover recent preclinical and clinical advances examining diverse new strategies to harness and engineer the function of cytokines for cancer immunotherapy. Example approaches include targeting of cytokines to tumor cells and host immune cells, optimizing the timing of cytokine dosing in combination therapies, and engineering cytokines for controlled serum half-life and tumor accumulation. These strategies offer the promise of new therapeutic regimens that can effectively drive innate and adaptive immune responses against cancer with greatly improved safety.
Early Phase 1 Clinical Trials
The scientific advancements in our understanding of the molecular machinery driving cancer have inevitably translated into breakthroughs in drug discovery. Among such breakthroughs are immune-based therapies, a number of which have demonstrated improved efficacy and durability of responses over traditional chemotherapies or targeted therapies and, as a result, have become reliable and innovative therapeutic options for select hematologic and solid cancers in recent years. The early drug development paradigm has traditionally involved preclinical characterization and testing of a candidate compound or agent, followed by evaluation of the safety and efficacy of the agent through rigorous clinical research, and ultimately obtaining regulatory approval to market the candidate drug. Of these steps, conducting clinical trials is arguably the most critical. Early phase clinical trials aim to assess the safety, tolerability, and dose of any investigational new anticancer drug. The high demand for patient access to cutting edge anticancer drugs, especially to immune-based therapies, and the recent surge in the efficiency of conducting clinical trials, continue to usher in changes in the present drug development process.
In this session, a comprehensive discussion of early drug development will be provided. Speakers will discuss relevant and promising phase I clinical trials on immunotherapeutic agents, either alone or in combination with other therapeutic interventions, and offer their insights on the future directions of immune-oncology treatments.
Immune Checkpoints— Beyond PD-1
The programmed cell death protein-1 (PD-1) immune checkpoint receptor plays an important role in regulating T cell responses and maintaining immune homeostasis. Binding of PD-1 with its ligand, programmed death-ligand 1 (PD-L1), dampens effector T cell responses. Inhibition of this interaction through application of anti-PD-1 or anti-PD-L1 antibodies provides a boosted immune response against cancer cells. However, while the PD-1/PD-L1 immune checkpoint has proven to be an effective target against malignant cells, many patients and tumor types still fail to respond to PD-1/PD-L1 blockade therapies. This segmented pattern of response following PD-1/PD-L1 inhibition has prompted further studies into the targeting of alternative immune checkpoints that regulate other aspects of host immunity. These ‘next generation’ of immune checkpoint targets, including LAG-3, Tim-3, and TIGIT, are currently being explored in clinical trials. Although these receptors belong to the same class of receptors as PD-1, they demonstrate unique functions and generate distinct immune responses across tissue sites. Increased understanding of the specialized functions of these other immune checkpoints will support the application of immunotherapies that target these receptors in the clinic.
This session will focus on the latest research regarding the biological function and targeting of LAG-3, Tim-3, and TIGIT, as well as the potential of targeting immune checkpoints that are specifically expressed on innate cells. Speakers will discuss unique aspects of each of these ‘new wave’ molecules in regulating immune response, including data demonstrating preclinical efficacy and translation into the clinic through clinical trials in cancer patients as both monotherapeutic agents as well as combination immuno-oncology strategies.
Metabolic Manipulation of the TME
Antibody-based therapies that target CTLA4 or PD1/PDL1 alone or in combination have demonstrated clinical efficacy in advanced cancers. Nevertheless a considerable proportion of patients remain unresponsive to these therapies (known as innate resistance) and amongst those who respond, a significant proportion develop acquired resistance and relapse. These suggests that multiple non-redundant immunosuppressive mechanisms co-exist within the tumor microenvironment (TME) and their rational co-targeting can increase the efficacy of host anti-tumor immunity. It is now recognized that the metabolic pathways activated or repressed in the TME create a barrier to anti-tumor immunity to favor tumor growth and progression.
This session will focus on strategies to reprogram the metabolic TME from one that is immunosuppressive to immune promoting. Speakers will discuss basic mechanisms of metabolism-centered immune-suppression and the use of therapeutic agents that inhibit immunosuppressive metabolites that can remodel a tolerogenic environment into one that is permissive to antitumor immunity and responsiveness to immunotherapy.
Myeloid Derived Suppressive Populations
T cell checkpoint inhibitors have been remarkably successful in harnessing the immune response and combating cancer. Notwithstanding, the success of T cell checkpoint inhibitors is currently limited to a few types of cancers, and even then, a large fraction of patients fail to benefit from these treatments. The efficacy of T cell checkpoint inhibitors can correlate with a pre-existing T cell anti-tumor response (T cell-inflamed tumors). Since innate immunity is an obligate prerequisite for adaptive immunity, we hypothesized that improving the innate immune response might extend the benefit of immunotherapy to non-T cell inflamed tumors. We have identified novel innate immune checkpoints driven by a subfamily of receptor tyrosine kinases (RTKs): TYRO3, AXL and MERTK (TAMs). These RTKs function in dendritic cells to limit antigen presentation and cytokine production. The same RTK family members also operate in macrophages to limit their inflammatory phenotype and promote their transition into tissue repair macrophages. We will describe the use of genetic ablation, including cell-type specific knockouts, of TAM receptors to dissect their molecular function in the anti-tumor response in mouse tumor models of melanoma and glioblastoma.
Myeloid cells are critical component of tumor microenvironment involved in regulation of immune responses in cancer as well as promotion of tumor progression and metastasis. Targeting of these cells is an attractive therapeutic option. Recent studies demonstrated that different populations of myeloid cells could compensate for each other and thus dampened the effect of therapy. Novel approaches for comprehensive targeting of myeloid cells in tumor sites are needed. Cancer is associated with expansion of pathologically activated monocytes and neutrophils-myeloid-derived suppressor cells (MDSC). This is gradual process closely linked to tumor progression. We have described that pathological activation of neutrophils is observed at early stages of cancer (MDSC-lice cells) and precede acquisition of full immune suppressive activity (MDSC stage). We will discuss genomic, functional, and metabolic characteristics of these cells.
Next Generation Bispecifics and Antibody-Like Molecules
Description coming soon.
Role of B Cells in Immunotherapy Toxicity
Immunotherapy has been impressively successful in multiple solid tumors, and in particular, blockade of the inhibitory PD1 molecule on CD8 and CD4 tumor infiltrating lymphocytes (TILs) has revolutionized standard of care in multiple cancers. However, anti-PD1 therapy only has about a 20% response rate in cancer patients, thus additional therapeutic approaches are clearly needed that will stimulate the anti-tumor immune response. Most studies to date have focused predominantly on T cells, with less consideration of tumor infiltrating B cells (TIL-Bs) despite their predominance in the tumor microenvironment (TME) and key role in the immune response. In fact, the major gap in TIL-B research is understanding the molecular targets that influence an anti- versus pro-tumor role for TIL-Bs in the TME. Further, an increased understanding of how TIL-Bs are targeted in current immunotherapies and how they could contribute to toxicity in patients is important for gaining a complete picture of the function of these immune cells in solid tumors.
This session will focus on the role of TIL-Bs in solid tumors and their function in immunotherapy and immunotherapy-related toxicity. Speakers will discuss data from preclinical models, patient primary tumors and emerging findings from clinical trials. Speakers will also discuss how to fill the research gap on TIL-Bs and how best to move forward with TIL-B focused immunotherapies alone or in combination with other therapies.
Understanding the Tumor Microenvironment
The tumor microenvironment is known as an immune suppressive environment and mediates upregulation of numerous immune inhibitory mechanisms, many of which are currently targeted by checkpoint blockade therapy. Besides upregulation of immune inhibition, the tumor microenvironment can also facilitate immune evasion through exclusion of T cells or dampen the anti-tumor immune response through yet unknown mechanisms. While several immune inhibitory functions of the tumor microenvironment are known to date many still remain elusive.
This session will discuss why understanding the molecular mechanisms of immune evasion within the tumor microenvironment is critical for the development and optimization of new therapies or combination therapies. The speakers will review four key areas of the tumor microenvironment and will discuss to which extent features of the tumor microenvironment are impacting the local anti-tumor immune response.