IMX

When dosed with an immunotherapy, adaptive and innate immune systems are activated, better allowing them to recognize disease cells in the body. However, the immune system also becomes more sensitive to self, potentially causing cytokine storm, macrophage activation syndrome, or autoimmunity. Predicting and preventing toxic effects in immunotherapies remains one of the biggest roadblocks in making these treatments a reality. The Inaugural Preventing Toxicity in Immunotherapy will examine effective preclinical models, biomarkers, and dosing considerations. The usefulness of preclinical models will also be debated with regards to humanized models vs. standard mouse models and cross reactivity. Finally, potential toxicity issues in combination therapies will be addressed. Overall, this event will enable researchers to continue moving forward rapidly, but safely.

MONDAY, APRIL 25

7:00 am Registration and Morning Coffee


BUILDING PRECLINICAL MODELS

8:30 Chairperson’s Remarks

Michelle Krogsgaard, Ph.D., Assistant Professor, New York University School of Medicine

8:40 Biophysical Engineering of Tumor Specific TCRs to Carefully Balance Tumor Reactivity and Autoimmunity in Cancer Immunotherapy

Michelle_KrogsgaardMichelle Krogsgaard, Ph.D., Assistant Professor, New York University School of Medicine

We are taking a variety of biophysical and cellular imaging approaches to determine how specific thresholds for T cell recognition of self (tumor)-antigens are set. Our recent results indicate that antitumor activity and autoimmunity are coupled and have a similar kinetic threshold; reducing autoimmunity cannot be accomplished without sacrificing efficacy of tumor killing. New strategies to overcome this issue include careful engineering of tumor-specific TCRs and T cell signaling pathways to balance tumor-reactivity and autoimmunity.

9:10 A Mouse Model for Adoptive T Cell Therapies with Engineered T Cell Receptors

Dave_KranzDavid M. Kranz, Ph.D., Phillip A. Sharp Professor, Biochemistry, University of Illinois

T cell receptors engineered for higher affinity against class I-restricted cancer antigens allow recruitment of both CD4 and CD8 T cells to the tumor. Adoptive T cell therapies with such TCRs can mediate significant efficacy, but also run the risk of off-target toxicities against structurally-related self-peptides. Engineering and comprehensive mutagenic scanning of several human TCRs will be described, along with the use of HLA-A2 transgenic mice in assessing possible safety issues.

9:40 Tumor Models to Investigate CAR T Cell Potency, Acute and Chronic Toxicity

David_GilhamDavid Gilham, Ph.D., Senior Lecturer, Clinical and Experimental Immunotherapy Group; ICS PGR Director, Institute of Cancer Sciences, University of Manchester

Reports of objective clinical responses and tumor regression in patients receiving Chimeric Antigen Receptor (CAR) T cell therapy are driving a major surge of interest in the field. CARs are artificial targeting proteins that exploit antibody-based approaches to re-direct the effector function of the T cell to virtually any cell surface target. However, it remains unclear whether toxicity resulting from over-activity of the T cell or lack of suitable target specificity is likely to be an issue. Models can provide some answer to this although the relevance of such models remains open to question.

10:10 Coffee Break

CYTOKINE STORM: Prediction, Diagnosis, and Management

10:45 Chairperson’s Remarks

Simon Lacey, Ph.D., Director, Translational and Correlative Studies Laboratory, Product Development and Correlative Sciences, University of Pennsylvania

10:50 Cytokine Storm Following CAR-T Cell Therapy: An Interdisciplinary Approach to Diagnosis and Symptom Management

Chrystal_LouisChrystal Louis, Ph.D., Co-Director, Neuroblastoma Program, Texas Children’s Hospital; Assistant Professor, Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine

Chimeric antigen receptor (CARs) positive T cells combines the specificity and anti-tumor effects of monoclonal antibodies with the direct cytotoxicity and long-term persistence of T cells. However, modifications designed to improve the affinity and anti-tumor activity of CARs increases the likelihood of on- and off-target toxicity secondary to low level antigenic expression on normal tissues. Toxicity associated with cytokine storm and macrophage activation syndrome can be life-threatening if not quickly identified and requires interdisciplinary communication and teamwork to successfully manage the symptoms.

11:20 Biomarkers Accurately Predict Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor (CAR) T Cell Therapy for Acute Lymphoblastic Leukemia (ALL)

Simon_LaceySimon Lacey, Ph.D., Director, Translational and Correlative Studies Laboratory, Product Development and Correlative Sciences, University of Pennsylvania

CAR T cells with anti-CD19 specificity have demonstrated remission rates as high as 90% in ALL patients treated with CTL019 (Maude et al., NEJM 2014), but cytokine release syndrome (CRS) can be a complication. We studied 43 cytokines, chemokines, and soluble receptors in 51 ALL patients treated with anti-CD19 CAR T cells. Biomarkers associated with severe CRS and predictive during the first 3 days after infusion of subsequent CRS4-5 compared to CRS0-3 were identified.

11:50 Managing Receptor-Engineered T Cell Cytokine Storms: Facts, Fabulations, Future Progress

Christopher_KlebanoffChristopher A. Klebanoff, M.D., Assistant Clinical Investigator, Center for Cancer Research, National Cancer Institute

Adoptive transfer of receptor-engineered T cells targeting tumor-associated antigens can mediate durable complete responses in patients with refractory solid and hematologic malignancies. In some cases, infusion of engineered T cells is associated with a spectrum of toxicities attributed to an exuberant release of cytokines. Dissemination of this promising treatment modality beyond specialized academic medical centers will require detailed understanding of both the pathogenesis and medical management of cell-related toxicities.

12:20 pm Sponsored Presentation (Opportunity Available)

12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:50 Session Break

2:20 Problem-Solving Breakout Discussions

Advantages and Disadvantages of Neoantigen Targeted TCR for Adoptive T Cell Therapy

Moderator: Michelle Krogsgaard, Ph.D., Assistant Professor, New York University School of Medicine

  • What are the conceptual and technical limitations in targeting tumor neoantigens for cancer immunotherapy?
  • How can we reliably select potent neoantigens for cancer immunotherapy?
  • Does the preclinical and clinical evidence support the effectiveness of targeting neoantigens?
  • Do neoantigens induce robust T-cell response and can this approach be applied to adoptive T-cell therapy or other immunotherapies?
  • Who will benefit from neoantigen targeted therapies?
  • Can we combine this therapy with other immunotherapies to obtain synergistic effects.

 

Critical Issues for Clinical Development

Moderator: Thomas Oliver Kleen, Ph.D., Executive Vice President, Immune Monitoring, Epiontis GmbH

 

  • Cost, logistics and sample requirements - reality versus the need for more functional data
  • Predictive, prognostic and pharmaco dynamics biomarkers – which do we need
  • Cell based immunity versus cytokines versus antibodies – to measure in circulation or tissue

 

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing


PLENARY KEYNOTE SESSION

4:00 Chairperson’s Remarks

4:10 The Promise of Cancer Immunotherapy: An Overview of Recent Advances and Jounce’s Approach to Delivering the Right Therapy to the Right Patient

Deborah_LawDeborah Law, D. Phil. CSO Jounce Therapeutics, Inc.

As immunotherapies become an increasingly important component of cancer treatment the challenge will be to identify ways to provide the best therapy(s) to the individual. This presentation will provide an overview of current cancer immunotherapies as well as highlight some of the challenges ahead including selection of optimal combinations, moving outside of T cell-directed approaches, and will highlight how Jounce Therapeutics is using its Translational Science Platform as an approach to develop and deliver the right therapy to the right patient.

4:50 Antibody as Drugs: Then, Now and Tomorrow

Paul_CarterPaul J. Carter, Ph.D., Senior Director and Staff Scientist, Antibody Engineering, Genentech

Antibodies have grown into a clinically and commercially important drug class with more than >45 antibodies marketed for imaging or therapy in the USA and/or Europe and with ~$63 billion in worldwide sales in 2013.  This presentation will highlight progress in developing antibody drugs and consider opportunities for future innovation.  


5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 End of Day

TUESDAY, APRIL 26

8:00 am Morning Coffee


IN VITRO EXPERIMENTS FOR TESTING CROSS REACTIVITY

8:25 Chairperson’s Remarks

Andrew K. Sewell, Ph.D., Distinguished Research Professor, Wellcome Trust Senior Investigator; Research Director, Institute of Infection and Immunity, Henry Wellcome Building, Cardiff University School of Medicine

8:30 ImmTACs: High Affinity T Cell Receptor-Based Bi-Functional Biologics for Redirected Tumor Killing

Joseph D. Dukes, Ph.D., Head, Preclinical Biology, Immunocore Ltd.

ImmTACs (Immune-mobilising monoclonal TCRs against cancer) are bi-specific reagents engineered to target tumor-specific antigens with high sensitivity and specificity, and then via an anti-CD3 antibody fragment redirect host T cells to promote tumor killing. Careful selection of tumor antigens and TCR engineering overcome the natural low affinity of tumor-specific antigens. Preclinical testing of ImmTAC (e.g. IMCgp100) specificity, efficacy and safety are determined through a detailed molecular and cellular testing programme. Clinical observations from IMCgp100 Phase I trial support our pre-clinical approach.

9:00 Preventing Self Reactivity of Engineered TCRs

Andy_SewellAndrew K. Sewell, Ph.D., Distinguished Research Professor, Wellcome Trust Senior Investigator; Research Director, Institute of Infection and Immunity, Henry Wellcome Building, Cardiff University School of Medicine

The αβ TCR repertoire is dwarfed by the vast array of potential foreign peptide-MHC complexes. Comprehensive immunity requires that each T cell recognizes numerous peptides and thus be extremely cross-reactive. Natural central tolerance culls T cells that have a high affinity for self peptide-MHC. TCR engineering bypasses this process and can result in dangerous self-reactivity. These toxicities can be predicted and engineered out without loss of specificity for the target antigen.

9:30 Preclinical Models that Inform Development of Bispecific Antibodies

Paurene_DuramadPaurene Duramad, Ph.D., MPH, DABT, Drug Safety & Pharmacometrics, Regeneron Pharmaceuticals, Inc.

Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. In this presentation, the preclinical mouse and non-human primate models used to inform development of a novel class of bispecific antibodies with native human immunoglobulin format will be described.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Awards


MONITORING THERAPIES IN REAL TIME

10:50 Next-Generation Immune Monitoring under ISO 17025 for Immuno-Oncology Trials and Biomarker Discovery

Thomas_KleenThomas Oliver Kleen, Ph.D., Executive Vice President, Immune Monitoring, Epiontis GmbH

Novel, targeted therapies rendered immune monitoring in clinical trials obligatory. Epigenetic-based, quantitative real-time PCR assisted cell counting (qPACC) under ISO 17025 allows quantification of immune cells from only small amounts of blood or tissue. T cells (Tregs), Th17 cells, Tfh cells, CD4+ and CD8+ cells, overall T cells (CD3+), B cells, NK cells (CD56 dim), neutrophil granulocytes and monocytes are the first examples of a next-generation of immuno-oncology biomarker tools that can be used in these settings.

11:20 Monitoring the Balance between Effector and Regulatory Immune Responses in Tumor Immunotherapy Clinical Trials

Brian_OlsonBrian M Olson, Ph.D., Assistant Scientist, University of Wisconsin Carbone Cancer Center

Clinical trials evaluating tumor immunotherapies have focused on monitoring the generation of anti-tumor effector immune responses. However, the evaluation of concurrent regulatory responses (mediated by the immune system or the tumor itself) is often overlooked, despite the critical role they can play in the clinical efficacy of these immunotherapeutic interventions. Studying these regulatory responses, researchers can potentially uncover approaches targeting both effector and regulatory immunity to more effectively treat cancer.

11:50 Toxicities Associated with Checkpoint Inhibitor Immunotherapy

Alexander_ShoustariAlexander N. Shoushtari, M.D., Medical Oncologist, Memorial Sloan Kettering Cancer Center


12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:20 Ice Cream Break in the Exhibit Hall with Poster Viewing


DOSING CONSIDERATIONS AND SCALING UP

2:00 Chairperson’s Remarks

Daniel W. “Trey” Lee, M.D., Assistant Clinical Investigator, St. Baldrick’s Scholar, Pediatric Oncology Branch, National Cancer Institute

2:05 Paving the Road Ahead for CD19 CAR T Cell Therapy: Avoiding the Big Potholes

Daniel_LeeDaniel W. “Trey” Lee, M.D., Assistant Clinical Investigator, St. Baldrick’s Scholar, Pediatric Oncology Branch, National Cancer Institute

CD19 CAR T cell therapy has produced complete response rates of 70-90% in children and young adults with refractory pre-B acute lymphoblastic leukemia across multiple institutions. Neurotoxicities and severe cytokine release syndrome, which can be lethal without timely and appropriate intervention, represent the biggest challenges in exporting this therapy to non-CAR centers. This presentation will describe these toxicities and outline a management algorithm and other strategies for minimizing severe effects while maximizing response.

2:35 Enhancing the Synthetic IQ of CAR T Cells

Michael_JensenMichael C. Jensen, M.D., Professor, Pediatrics; Adjunct Professor, Bioengineering, University of Washington School of Medicine; Director, Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute; Joint Member, Program in Immunology, Fred Hutchinson Cancer Research Center

The potential of immunotherapy to become a mainstream component of treatment for pediatric oncology patients is substantial. Emerging clinical data is depicting both the impressive potency as well as toxicities of CAR T cell therapy for ALL. The Jensen lab is focused on developing next generation T cells that are engineered with components that facilitate precise control of their function and fate. Our goal is to deliver on precision therapy that is controlled from the bedside to enhance both efficacy and safety of this therapeutic modality.

3:05 Switch Mediated Activation and Re-Targeting of CAR-T Cells

Travis_YoungTravis Young, Ph.D., Principal Investigator, Immuno-Oncology, California Institute for Biomedical Research (Calibr)

Chimeric antigen receptor T (CAR-T) cell therapy has produced remarkable results in clinical trials for patients with ALL and CLL leukemia. However, challenges related to the inability to control CAR-T cells once infused into the patient has caused severe cytokine release syndrome, and the inability to terminate the response has caused long term B-cell aplasia for CD19 targeted CAR-Ts. Towards overcoming these challenges we have developed a two component system in which the activity of bio-orthogonal "switchable" CAR-T (sCAR-T) cells is controlled by dosing of an antibody-based switch. The switch controls activation of the sCAR-T cell through a peptide neo-epitope (PNE) engrafted in the antibody scaffold. The PNE is bound exclusively by the sCAR, allowing the switch to mediate the formation of structurally defined and temporally controlled immunological synapses between the sCAR-T cell and target cell. In this way, the activation and cytokine release of the sCAR-T cell is fully tunable by dosage of the switch. We have demonstrated the efficacy of this approach is comparable to conventional CAR-T cells in xenograft models for leukemia, acute myelogenous leukemia, lymphoma, and a breast cancer cells with a range of antigen densities, while affording titratable levels of cytokines. In addition we have demonstrated the same sCAR-T cell can be iteratively retargeted to multiple antigens which we expect will be useful in preventing antigen-loss relapse. This is expected to confer greater safety and versatility in clinical translation, as well as establish a single universal sCAR-T cell which can be used across a broad range of antigens/tumor targets.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:25 PANEL DISCUSSION: The T Cell Therapy Race: How to Advance Safely

Moderator: Christopher A. Klebanoff, M.D., Assistant Clinical Investigator, Center for Cancer Research, National Cancer Institute

Panelists: Simon Lacey, Ph.D., Director, Translational and Correlative Studies Laboratory, Product Development and Correlative Sciences, University of Pennsylvania

Michael C. Jensen, M.D., Professor, Pediatrics; Adjunct Professor, Bioengineering, University of Washington School of Medicine; Director, Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute; Joint Member, Program in Immunology, Fred Hutchinson Cancer Research Center

Daniel W. “Trey” Lee, M.D., Assistant Clinical Investigator, St. Baldrick’s Scholar, Pediatric Oncology Branch, National Cancer Institute

  • Who, what, where
  • Location, location, location
  • Cooling the flames
  • Neurotoxicity associated with anti-CD19 targeted therapies
  • Engineering safety

5:25 End of Preventing Toxicity in Immunotherapy


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