Catherine Bollard, MD of Washington Children’s Hospital
Daniel Powell, PhD of University of Pennsylvania
Some of the most exciting results in cancer medicine, in the last decade, have come about by treating relapsed patients with B cell lymphoma with their own T cells that have been modified to attack the tumor cells. T cells in the body form part of the cellular immune response and they normally carry out a very important role in killing cells that are infected with viruses. These cells can be modified in the laboratory using sophisticated molecular techniques to change their specificity so that they can attack tumor cells. Once the cells are expanded in the laboratory they can be reintroduced into the patient and they target the cells one wants to eliminate. This technology has been around in one form or another for over fifteen years, but it now looks as if researchers have arrived at a watershed where the therapy appears to work really efficiently for this disease. Unfortunately, there are no markers available today that avoids the T cells attacking the patients normal as well as malignant cells and this may be a significant problem in the future.
Many questions remain concerning this new form of personalized medicine. Will it work for other cancers, particularly solid tumors where access of the T cells to the malignant tissues is more difficult to achieve. Many tumors also produce factors that inhibit T cell function so how does one deal with this? Apart from these questions there are others regarding the residence time of the modified T cells in the body, whether they are immunogenic and can the therapy be repeated. Finally, there is a question as to whether this type of therapy can be converted into one that is available outside of an academic research setting.
The topic of immune therapy is one that fits perfectly with the rationale underlying the Forbeck Foundation think tank meetings. I cannot think of a topic that is better suited to bring together basic researchers in molecular biology and immunology with clinical colleagues to try and solve some of the problems eluded to above. Input from industry will also be encouraged. If this is possible and the early clinical results prove to be substantiated then we may be on the brink of changing the treatment of specific cancers, using the bodies own cells to attack the tumor as compared to use of more toxic chemotherapeutic regimens.
The 2015 Forum was focused on Cancer Immunotherapy. Major topics of the forum included (i) cellular therapies using antigen specific and gene-modified T cells for targeting leukemia and solid tumors; (ii) overcoming hurdles and barriers with regard to immunogenicity, immune escape, and the role of tumor microenvironment; (iii) vaccine strategies and antigen presentation; (iv) the role of immune cells in allogeneic transplantation; and (vi) current antibody/combination approaches for the treatment of pediatric malignancies. During the past decade, major advances have been made in improving the efficacy of these modalities and regulatory hurdles have been taken. Nevertheless, there is still a long way to go to fully exploit the potential of immunotherapeutic strategies to improve the cure of children and adolescents with malignancies. This forum supported new collaborations and insights for further translational and clinical immunotherapy studies.
The first speaker Dr. Klebanoff discussed how there is excitement in the field with the adoptive transfer of gene-engineered T cells expressing chimeric antigen receptors (CARs) targeting CD19, that some of the oldest and most durable successes have been utilizing tumor infiltrating lymphocytes (TILs) for melanoma and how this field has dramatically improved our knowledge regarding the basic immunobiology of cancer and how this information will aid in the development of newer T-cell therapeutics for solid tumors. Dr. Klebanoff also noted the increased focus of the field towards more highly personalized immunotherapy approaches.
Dr. Hwu then provided his broad experience using TILs for melanoma and how this therapy has been greatly enhanced using combination immunobiologics, most critically the checkpoint inhibitors. Given the “off the shelf” nature of such inhibitors, it should be possible one day for the vast majority of patients to benefit from immunotherapy. Dr. Hwu also discussed the use of biomarkers that could be used to identify which patients are more likely to respond to TIL therapy and checkpoint inhibitors. Dr Hwu emphasized the fact that the systematic and methodical optimization of manufacturing the most effective T-cell products would be required for this approach to become scalable for the treatment of common cancers. Finally, Dr. Hwu stressed the need for a return to studies of vaccines for the treatment of cancer.
Dr. Busch provided more basic insights into the power of the T cell. His laboratory has demonstrated that a defined T cell subset (central memory T cells) is essential for robust and long-term responses after infusion. This finding explains why even very low numbers of infused T cells can be sufficient (in the extreme, a single T cell) to reconstitute protective immunity against cancer and/or viruses. His work is now identifying which T cell markers can be used to select for T cell use in therapy that have the greatest potential to eradicate disease. Dr. Busch provided reports from several ongoing clinical trials using purified T cell products for the treatment of infections after allogeneic stem cell transplantation or after genetic modification for the treatment of cancer.
Dr. Riddell then provided new information demonstrating remarkable remissions in heavily treated patients with acute lymphoblastic leukemia even in the adult population. He showed that T-cell products should ideally be derived from the central memory T cell population and should have a fixed CD4:CD8 T cell ratio. He therefore provided convincing data that determining the characteristics that are desired in the starting T cell population, and analyzing the persistence, migration, metabolic fitness, function and fate of transferred T cells, is critically important when monitoring patients who have received T cell therapies so that we can learn what makes a T cell the most effective therapy for killing cancer cells.
Under the selective pressure of a competent immune response, cancers and viruses are prone to become resistant to the immune system. One straightforward approach to avoid tumor or virus induced immune escape is administration of T-cells very early in the disease course, while targeting multiple virus- and tumor-associated antigens can reduce the risk of escape due to loss of antigen presentation. Dr Bollard, therefore, highlighted various clinical trials utilizing these approaches for hematologic malignancies and virus-associated diseases.
Dr. Savoldo then highlighted several gene therapy approaches to overcome tumor immune evasion with a specific focus on Hodgkin’s Lymphoma, CLL and neuroblastoma. Dr. Savoldo discussed that chimeric antigen receptor (CAR) T cells are sensitive to immune checkpoint inhibitors. Given this, genetic approaches might be applied to render T cells for therapy less sensitive to checkpoint inhibition.
Dr. Hourigan provided an overview based on his unique experience in Acute Myeloid Leukemia (AML) demonstrating that AML is oligoclonal even within an individual patient, with the clone predominant at first presentation not necessarily the same as the one responsible for post treatment disease relapse and death. He highlighted how AML may be the ideal disease to study tumor evasion strategies and that while there is no single antigen suitable for immune targeting in every AML patient, that every AML patient has at least one antigen that can be targeted with immune therapy. He rationalized that the best targeted immunotherapies for AML Session II Overcoming Immune Evasion Strategies 4 should, therefore, target multiple antigens, not a single antigen.
Dr. Fry then expanded on the CAR T cell therapy initially discussed by Dr Riddell. Most critically he highlighted other targets being evaluated such as CD22 for pediatric ALL as well as the development of cytokine receptors with functional importance for the leukemic cell.
Dr. Gottschalk then expanded on the use of the CAR technology for solid tumors such as pediatric brain tumors and osteosarcomas. He highlighted the fact that the success of CARs in the setting of solid tumors has been hampered by a lack of unique tumor associated antigens, inefficient homing of T cells to tumor sites and the immunosuppressive microenvironment and discussed the strategies that have been and should be undertaken to improve outcomes for pediatric patients with solid tumors.
Dr. Powell then developed this field further identifying other strategies to improve CAR T cell therapies for solid tumors. He discussed the identification of new “safe” tissue specific antigens that represent “druggable” and effective antigens expressed by the tumor, the tumor vasculature or immunosuppressive cellular elements in the tumor microenvironment. Dr. Powell discussed the building of multivalent T cells that address tumor antigen heterogeneity and antigen loss and the development of in vivo model systems that mimic these challenges in order to design and test new strategies for the creation of potent and safe CAR T cell therapy for common solid cancers.
Dr. Jensen then discussed his laboratory’s work which focuses on T-cell genetic modification for re-directing antigen specificity to tumors utilizing CARs as well as the evolution of multifunctional cytoplasmic signaling domains developed for these chimeric antigen receptors (CARs) that provide dual activation and costimulatory signaling. He also discussed the increasingly broad array of genetic manipulations including not only transgene insertion, but also targeted gene knock out using engineered targeted nucleases such as TALEN’s and ZFN. He highlighted the fact that the next decade of advances in this arena will depend on iterative bench-to-bedside back-to-the-bench translational studies capable of sustaining the evolution of these technologies in the context of clinical parameters relevant to the pediatric oncology patient population.
In the final session, Dr. Wargo discussed how to better identify predictors of response to immune checkpoint blockade (and other forms of cancer immune therapy). She stressed that the longitudinal collection of tumor specimens from donors was critical to the discovery of predictors of response. Dr, Wargo pointed out that genomic and immune heterogeneity can influence tumor growth and response to therapy. She then effectively showed how insights gained through these investigations will inform studies in patients with earlier stage cancer. Finally, she discussed novel strategies to enhance responses to immune therapy such as through modulation of the gut microbiome.
Dr. Kean then built on her wealth of expertise in the biology of hematopoietic stem cell transplantation (HCT) and graft-versus-host disease (GVHD). She addressed three critical questions in the field: (1) What are the mechanisms that drive breakthrough T cell allo-activation and tissue damage despite current immune suppression strategies? (2) Can we design treatment strategies to directly target these mechanisms? and (3) What are the necessary components of a GVHD-prevention strategy that will safely produce long-term immune tolerance? To answer these questions, and thus to uncover the mechanisms driving the pathogenesis of T cell activation and tissue invasion, Dr Kean’s group has undertaken a major initiative to use a systems biology approach to define the T cell-centric GVHD transcriptome. The Non-Human Primate GVHD Transcriptome Project has allowed her to identify novel molecular pathways active in GVHD, many of which represent “druggable” targets for which candidate interventions are immediately available. Her results are providing a comprehensive map of the gene expression networks that control T cell activation, antigen recognition and tissue invasion. Importantly, the lessons from these GVHD-inducing T Cells ‘Gone Wrong’ can be used to harness T cell activation and survival pathways for the right reason: effective T cell immunotherapy for cancer eradication. These lessons might also aid in our understanding of the mechanism accounting for toxicity, such as cytokine release syndrome, that is sometime observed in patients receiving adoptive T cell therapy.
In the final session Dr. Dudley provided a commercial perspective of how to move the novel therapeutics discussed during the course of the Forum from Phase I clinical trials to commercialization. The transition from Phase 1 to commercial manufacturing usually requires substantial increase in the quality of reagents and equipment, establishment of reliable and harmonized release (potency) assays, introduction of efficiencies into the manufacturing workflow, and reduction of the cost of goods. Sponsors are incentivized to demonstrate consistency, manufacturing scalability and profitability, while maintaining product efficacy. Introducing process changes into an established cell product can be challenging because critical quality attributes or key process parameters may be altered or poorly characterized. Additionally, if potency assays are not predictive of clinical outcome and suitable animal models are not available for safety testing, then major process changes need to be vetted through clinical trials in patients. Therefore, he emphasized that the strategic use of small cohort “pilot” studies for discovery and development can enable efficient target discovery, process change and commercial product scale out.
Conclusions and Outlook
The Forbeck Forum offered a unique environment to openly discuss the latest advances as well as the challenges associated with the development of novel immunotherapies for pediatric cancer. Based upon the recent developments and the clinical data that was shared, it was surmised this is an era of profound hope for pediatric and adult patients with cancer. Since the last Forbeck Forum focused on Cancer Immunotherapy gathered in 2008, the field has witnessed 90% cancer remission rates following CAR T cell therapy in patients with childhood and adult acute lymphoblastic leukemia, the reproducibility of adoptive T cell therapy induced cancer regressions in melanoma, synovial sarcoma and lymphoma, and the FDA approval of immune checkpoint inhibitors as well as cancer vaccines. Even lung cancer has joined the cadre of immune responsive cancers. Still, not all patients respond to immune therapy and it was agreed by the group that there was much work remaining to be done if these dramatic cancer remissions are to be achieved more reproducibly and in other cancer types. Discussions were spirited and launched new collaborations aimed at answering some of the important questions in the field.
Esra Akbay, PhD
Dana Farber Cancer Institute
Angelika Amon, PhD
Massachusetts Institute of Technology
Catherine Bollard, MD
Children's National Health System The George Washington University
University of Munich
Mark Dudley, PhD
Terry Fry, MD
National Cancer Institute
Steve Gottschalk, MD
Texas Children's Hospital
Chris Hourigan, MD
Patrick Hwu, MD
MD Anderson Cancer Center
Leslie Kean, MD, PhD
Seattle Children's Hospital
Christopher Klebanoff, MD
Annette Kunkele, MD
Charite - University Hospital Berlin
Shannon Maude, MD
Children's Hospital of Philadelphia
Daniel Powell, PhD
University of Pennsylvania
Stanley Riddell, MD
Fred Hutchinson Cancer Research Center
Barbara Savoldo, MD, PhD
University of North Carolina
Stefani Spranger, PhD
University of Chicago
Paul Tumeh, MD
University of California Los Angeles
Jennifer Wargo, MD
MD Anderson Cancer Center