Click here to learn about Academy events, publications and initiatives around COVID-19.

We are experiencing intermittent technical difficulties. At this time, you may not be able to log in, register for an event, or make a donation via the website. We appreciate your patience, and apologize for any inconvenience this may cause.

Our site is under planned maintenance. At this time, you will not be able to log in, register for an event, or make a donation via the website. We appreciate your patience, and apologize for any inconvenience this may cause.

Support The World's Smartest Network
×

Help the New York Academy of Sciences bring late-breaking scientific information about the COVID-19 pandemic to global audiences. Please make a tax-deductible gift today.

DONATE
This site uses cookies.
Learn more.

×

This website uses cookies. Some of the cookies we use are essential for parts of the website to operate while others offer you a better browsing experience. You give us your permission to use cookies, by continuing to use our website after you have received the cookie notification. To find out more about cookies on this website and how to change your cookie settings, see our Privacy policy and Terms of Use.

We encourage you to learn more about cookies on our site in our Privacy policy and Terms of Use.

Frontiers in Cancer Immunotherapy 2021

WEBINAR

Only

Frontiers in Cancer Immunotherapy 2021

Wednesday, May 12, 2021, 10:30 AM - Friday, May 14, 2021, 5:00 PM EDT

Virtual Symposium

Presented By

Cancer Discussion Group

The New York Academy of Sciences

 

In the decade since the approval of the first checkpoint inhibitor, immunotherapy has shifted the paradigm for cancer treatment, delivering effective and durable responses for numerous patients. During that time, combination therapies, adoptive cell therapies, and cancer vaccines have further expanded the impact of immunotherapy.  Nonetheless, challenges remain in understanding why some tumor types are refractive to immunotherapy and how to better predict patient responses to treatment.  This three-day conference will convene experts in immuno-oncology to discuss the latest research in the field. Topics under consideration will include how insights from the immune response to infection can inform our understanding of cancer immunotherapy, the COVID-19/Immuno-oncology interface, advances in multiple myeloma, cytokines, novel checkpoints and more.

Registration

Member
$90
Nonmember Academia, Faculty, etc.
$195
Nonmember Corporate, Other
$255
Nonmember Not for Profit
$195
Nonmember Student, Undergrad, Grad, Fellow
$135
Member Student, Post-Doc, Fellow
$45
Deadline:
0
days
left

Keynote Speakers

Irving Weissman, MD
Irving Weissman, MD

Stanford University

Padmanee Sharma, MD, PhD
Padmanee Sharma, MD, PhD

MD Anderson Cancer Center

Crystal L. Mackall, MD
Crystal L. Mackall, MD

Stanford University

Speakers

Paolo Ascierto, MD
Paolo Ascierto, MD

Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli

Juliet Barker
Juliet Barker, MBBS

Memorial Sloan Kettering Cancer Center

Chiara Bonini
Chiara Bonini, MD

Università Vita-Salute San Raffaele, Milan

Adelheid Cerwenka
Adelheid Cerwenka, PhD

Heidelberg University

George Coukos
George Coukos, MD, PhD

University of Lausanne

Kristen M. Hege, MD
Kristen M. Hege, MD

Bristol Myers Squibb

Katherine Hsu
Katherine Hsu, MD, PhD

Memorial Sloan Kettering Cancer Center

Eric L Smith
Eric Smith, MD, PhD

Dana Farber Cancer Institute

Ann Leen
Ann Leen, PhD

Baylor College of Medicine

Jeffrey Miller
Jeffrey Miller, MD

University of Minnesota

Richard O'Reilly
Richard O'Reilly, MD

Memorial Sloan Kettering Cancer Center

Charles Swanton
Charles Swanton, FRS

The Francis Crick Institute

Harlan Robins
Harlan Robins, PhD

Adaptive Biotechnologies

Jaume Pons
Jaume Pons, PhD

ALX Oncology

Bob Uger
Bob Uger, PhD

Trillium Therapeutics

John Wherry, PhD
John Wherry, PhD

University of Pennsylvania

Kate Sasser, PhD
Kate Sasser, PhD

Genmab

Shannon Turley, PhD
Shannon Turley, PhD

Genentech

Ben Greenbaum
Ben Greenbaum, PhD

Memorial Sloan Kettering Cancer Center

Nina Bhardwaj
Nina Bhardwaj, MD, PhD

Icahn School of Medicine at Mount Sinai

Willem Overwijk
Willem Overwijk, PhD

Nektar Therapeutics

Marc Theoret
Marc Theoret, MD

US Food and Drug Administration (FDA)

Suzanne L. Topalian
Suzanne L. Topalian, MD

Johns Hopkins School of Medicine

Bronwen E. Shaw, MD, PhD
Bronwen E. Shaw, MD, PhD

Medical College of Wisconsin

Frances Balkwill, PhD
Frances Balkwill, PhD

Queen Mary University of London

Sara Pai, MD, PhD
Sara Pai, MD, PhD

Harvard Medical School, Massachusetts General Hospital

Scientific Organizing Committee

Chris Boshoff, MD, PhD
Chris Boshoff, MD, PhD

Pfizer

Renier Brentjens, MD, PhD
Renier Brentjens, MD, PhD

Memorial Sloan Kettering Cancer Center

Padmanee Sharma, MD, PhD
Padmanee Sharma, MD, PhD

MD Anderson Cancer Center

George Zavoico, PhD
George Zavoico, PhD

Cue Biopharma

Sara Donnelly, PhD
Sara Donnelly, PhD

The New York Academy of Sciences

Sonya Dougal, PhD
Sonya Dougal, PhD

The New York Academy of Sciences

Barbara Knappmeyer, PhD
Barbara Knappmeyer, PhD

The New York Academy of Sciences

Grant Support

Supported by a grant from Genentech, a member of the Roche Group.​

AstraZeneca has provided a sponsorship grant towards this independent Programme.


Wednesday

May 12, 2021

10:30 AM

Introduction and Welcome Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences

Opening Keynote

10:40 AM

Unraveling Mechanisms of Response and Resistance to Immune Checkpoint Therapy

Speaker

Padmanee Sharma, MD, PhD
MD Anderson Cancer Center

Immune checkpoint therapy has revolutionized cancer treatment, but there are many unanswered questions pertaining to mechanisms of response and resistance. In an attempt to address some of these questions, Dr. Sharma focuses her effort on a “reverse translation” process. She studies human immune responses to generate hypotheses related to mechanisms of tumor rejection, which she tests in appropriately designed pre-clinical models, and subsequently uses the new data to design novel clinical trials to improve outcomes for patients with cancer. For example, Dr. Sharma designed and conducted the first neoadjuvant (pre-surgical) trial with immune checkpoint therapy (anti-CTLA-4) in 2006. These studies in patients with localized bladder cancer led her to identify the ICOS/ICOSL pathway as a novel target for cancer immunotherapy strategies. This initial trial provided the first safety data for administration of immune checkpoint therapy in the neoadjuvant setting, which led to many other neoadjuvant studies. This trial was also the first demonstration of anti-tumor responses with immune checkpoint therapy for patients with bladder cancer, which led to many other clinical trials in patients with bladder cancer, including clinical trials with anti-PD-1 (nivolumab) that were led by Dr. Sharma and her colleagues, thereby enabling FDA-approval of nivolumab for patients with metastatic bladder cancer. In addition, Dr. Sharma demonstrated for the first time that human tumors express VISTA as an immunosuppressive pathway, which acts as a resistance mechanism to anti-CTLA-4 therapy. Clinical trials targeting VISTA are now ongoing. Dr. Sharma was also the first to demonstrate that anti-CTLA-4 plus inhibition of EZH2 can improve anti-tumor responses, which led her to design a new clinical trial with this combination. This clinical trial is currently accruing patients. More recently, Dr. Sharma demonstrated for the first time that the unique immunologic niche within a specific organ, such as bone, impacts response to treatment with immune checkpoint therapy. Dr. Sharma will discuss data from her research studies.

Session 1: Viral Immunology and COVID-19

11:25 AM

What COVID-19 and Driver Genes Teach us about Quantifying Immune Recognition

Speaker

Ben Greenbaum, PhD
Memorial Sloan Kettering Cancer Center
12:05 PM

Management of Melanoma Patients During the COVID-19 Pandemic

Speaker

Paolo Ascierto, MD
National Tumor Institute Fondazione G. Pascale, Naples
12:35 PM

Lunch Break

1:05 PM

Virtual Poster Session 1

Session 2: Short Talks

Session Chairperson
Barbara Knappmeyer, PhD, The New York Academy of Sciences
2:00 PM

Lifileucel (LN-144), a Cryopreserved Autologous Tumor Infiltrating Lymphocyte (TIL) Therapy in Patients with Advanced (Unresectable or Metastatic) Melanoma: Median Duration of Response Not Reached at 28 Month of Study Follow-up

Speaker

Maria Fardis, PhD
Iovance Biotherapeutics

Treatment options are limited for advanced melanoma patients who progress after or do not respond to immune checkpoint inhibitors (ICI) and targeted therapies. Lifileucel is an adoptive cell therapy using TIL that has shown efficacy in patients with advanced melanoma who have progressed on/after anti-PD1 (Sarnaik 2020).  C-144-01 (NCT02360579) is a global Phase 2, multicenter study of lifileucel in advanced melanoma patients who have progressed on anti-PD1 therapy and BRAFi/MEKi, if BRAF V600 mutant. We report on Cohort 2 (N = 66) patients. Tumors were resected locally, shipped to central GMP facilities for manufacturing of TIL in a 22-day process. Therapy consisted of nonmyeloablative lymphodepletion (cyclophosphamide / fludarabine), a single lifileucel infusion, followed by up to 6 doses of IL-2. Objective response rate (ORR) was based on RECIST1.1. Data cutoff: 14Dec2020.  Baseline characteristics: 3.3 mean prior therapies (100% anti-PD1; 80% anti-CTLA4; 23% BRAFi/MEKi), high baseline tumor burden (106 mm mean target lesion SOD), 42% liver/brain lesions, 41% LDH > ULN. ORR by Investigator was 36.4% (3 CR, 21 PR). One patient converted from PR to CR at 24 mo. post-therapy. Median DOR was still not reached at median follow-up of 28 month of study follow up, and 11 patients (17%) had further SOD reduction since previous data cut of Apr2020.   Iovance is investigating lifileucel in earlier disease settings, in combination with ICI, and in other metastatic solid malignancies.

2:15 PM

Targeting Thrombospondin-1/CD47 Signaling Potentiates Anti-Tumor Immune Responses by Modulation of Cellular Bioenergetics

Speaker

Elizabeth Stirling, MS
Wake Forest School of Medicine

CD47 is an integral membrane protein that alters adaptive immunosurveillance when bound to the matricellular glycoprotein thrombospondin-1 (TSP1). We examined the impact of the TSP1/CD47 signaling axis on melanoma patient response to anti-PD1 therapy due to alterations in T cell activation, effector function and bioenergetics. An increase in T cells expressing CD47 and circulating levels of TSP1 post-anti-PD1 treatment was observed in non-responding patients compared to responding. Malignant melanoma patient biopsies also have increased CD47 expression compared to normal tissue. Therefore, TSP1/CD47 expression could serve as a marker to predict patient response to immune checkpoint blockade therapy. Additionally, TSP1 limited cytotoxic (CD8+) T cell effector function against melanoma cells; however, targeting CD47 allowed T cells to overcome this TSP1 interaction, sustaining activation and effector function. CD47 targeted naïve and activated CD8+ T cells have enhanced mitochondrial function and glycolysis compared to wild type, suggesting CD47 mediated metabolic reprogramming of T cells. A 50% decrease in tumor burden was observed by targeting CD47 in a syngeneic B16 melanoma model due to increased tumor oxygen saturation and granzyme B secreting CD8+ T cells. Therefore, the expression of TSP1/CD47 may serve as markers of immune checkpoint blockade response, and targeting this pathway may preserve T cell activation, effector function, and bioenergetics to reduce tumor burden.

Session 3: Immune Responses and Virus Specific T Cells

Session Chairperson
George Zavoico, PhD, Cue Biopharma
2:30 PM

Immune Responses to COVID-19

Speaker

John Wherry, PhD
University of Pennsylvania
3:00 PM

Moving Towards Personalized T Cell Therapy

Speaker

Harlan Robins, PhD
Adaptive Biotechnologies
3:30 PM

T Cell Therapy for Viruses

Speaker

Ann Leen, PhD
Baylor College of Medicine
4:00 PM

Break

4:10 PM

Genetically Engineering Virus Specific T Cells

Speaker

Richard O’Reilly, MD
Memorial Sloan Kettering Cancer Center

Adoptive transfer of transplant donor-derived virus-specific T-cells is well recognized as a potentially curative therapy for EBV lymphomas, drug-refractory CMV infections and severe adenovirus, BK and JC infections. However, their application is limited by the time required for generating the T-cells and their cost. We have developed banks of EBV and CMV-specific T-cells, from healthy 3rd party donors, each characterized as to HLA type, virus-specificity, and HLA restriction. In our trials, such T-cells have induced durable remissions 68% of monoclonal Rituxan resistant EBV lymphomas developing in HCT recipients and 54% of solid organ transplant recipients who have failed Rituxan and CHOP chemotherapy. The method used to generate these T-cells also depletes alloreactive T-cells such that the risk GVHD or graft rejection is obviated. When engineered to express a tumor-reactive CAR, or TCRs mimic these EBVCTLs exhibit potent activity in animal models against hematologic malignancies. In early phase clinical trials, CAR-modified EBV-specific T-cells generated from patients or their HCT donors, have exhibited minimal toxicity and, in some cases, significant but short-term anti-tumor activity. At our center, early, ongoing trials of 3rd party-donor derived CAR modified EBVCTLs have shown particular promise in the treatment of refractory lymphomas, again with minimal risk of toxicities, cytokine release syndrome or GVHD. In this presentation, we will review the attributes and limitations of CAR-modified virus-specific T-cells and strategies being explored to enhance their immediate accessibility, broad applicability, effective anti-tumor activity and in vivo persistence.

Session 4: Neoantigens and Cancer Vaccines

Session Chairperson
George Zavoico, PhD, Cue Biopharma
4:40 PM

Overcoming Resistance to Immunotherapy: Targeting Innate Immune Cells

Speaker

Nina Bhardwaj, MD, PhD
Icahn School of Medicine at Mount Sinai
5:10 PM

Day 1 - Closing Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences
5:15 PM

Adjourn Day 1

Thursday

May 13, 2021

10:30 AM

Welcome Back Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences

Session 5: Cytokines

Session Chairperson
Padmanee Sharma, MD, PhD, MD Anderson Cancer Center
10:35 AM

Cell Therapies and Cytokines

Speaker

George Coukos, MD, PhD
University of Lausanne
11:05 AM

Modelling and Targeting the Ovarian Cancer Tumor Microenvironment

Speaker

Frances Balkwill, OBE, FMedSci
Barts Cancer Institute, Queen Mary University of London
11:35 AM

Break

11:45 AM

Harnessing NK Cells Against Cancer Through IL-15 Pathway Activation

Speaker

Willem Overwijk, PhD
Nektar Therapeutics
12:15 PM

TGF-Beta

Speaker

Shannon Turley, PhD
Genentech
12:45 PM

Lunch Break

Keynote Lecture

1:15 PM

Normal and Neoplastic Stem Cells

Speaker

Irving Weissman, MD
Stanford University

We isolated mouse then human hematopoietic stem cells (HSCs). Transplantation of purified HSCs regenerates the blood and immune systems without graft vs. host disease, can induce transplant tolerance to tissues from the donor. In metastatic breast cancer patients post myeloablative chemotherapy, HSC purification allowed autologous transplantation of cancer-free grafts. The 15-year overall survival rate was ~33% in recipients of cancer-free HSCs.

To study the relationship between stem cells and cancer, we followed the preleukemic progression from hematopoietic stem cells (HSCs) to myelogenous leukemias, and found that the developing pre-cancerous HSC clones gradually accumulate mutations, with the last mutation giving rise to leukemia stem cells (LSC). The LSCs have acquired self-renewal and evaded programmed cell death and programmed cell removal.

A checkpoint inhibitor for innate immunity macrophages: Comparing LSC to HSC, we identified CD47 overexpression on LSC, then all cancers tested, and showed that it is used by cancer cells to evade macrophage phagocytosis by binding to SIRP alpha, its inhibitory receptor on macrophages. CD47 is the first target that is expressed on all human cancers tested. Humanized IgG4 anti-CD47 Abs are in clinical trials. anti-CD47 combination with Rituximab led to responses of aggressive lymphomas, relapsed and refractory to Rituxan and chemotherapy. The combined response rate was nearly 50%, 70-80% of these achieved complete remission.

Session 6: CD47 and SIRP Alpha

Session Chairperson
Renier Brentjens, MD, PhD, Memorial Sloan Kettering Cancer Center
2:00 PM

CD47-A Clinically Validated Myeloid Checkpoint

Speaker

Jaume Pons, PhD
ALX Oncology

CD47 is a widely expressed glycoprotein of the immunoglobulin superfamily that plays a critical role in self-recognition. Various solid and hematologic cancers exploit CD47 expression in order to evade immunological eradication, and its overexpression is clinically correlated with poor prognoses. CD47 interacts with signal regulatory protein-alpha (SIRPα) expressed on myeloid cells, transmitting inhibitory signals that regulate DC homeostasis, self-recognition, and macrophage-mediated phagocytosis. Given its essential role as a myeloid checkpoint for innate immunity and subsequent adaptive immunity, CD47-SIRPα axis has been explored as a new target for cancer immunotherapy. In this talk we will describe mechanistic insights into therapeutic modulation of the CD47 pathway and emerging clinical validation.

2:30 PM

Targeting CD47 with SIRPaFc Fusion Proteins

Speaker

Bob Uger, PhD
Trillium Therapeutics
3:00 PM

Break

Session 7: Assessment of Response

Session Chairperson
Chris Boshoff, MD, PhD, Pfizer
3:10 PM

Assessment of Response

Speakers

Moderator: Chris Boshoff, MD, PhD
Pfizer
Priya Bhosale, MD
MD Anderson Cancer Center
Sara Pai, MD, PhD
Harvard Medical School, Massachusetts General Hospital
Marc Theoret, MD
US Food and Drug Administration (FDA)
Suzanne L. Topalian, MD
Johns Hopkins School of Medicine

Session 8: Multiple Myeloma

Session Chairperson
Chris Boshoff, MD, PhD, Pfizer
3:55 PM

Next Generation Approaches Targeting CD38 in Cancer Therapy

Speaker

Kate Sasser, PhD
Genmab
4:25 PM

BCMA Directed Cell Therapies for Multiple Myeloma

Speaker

Kristin M. Hege, MD
Bristol Myers Squibb

B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor superfamily that has restricted expression on malignant and normal plasma cells making it a high priority target for novel multiple myeloma therapies. Numerous therapeutic approaches targeting BCMA are in clinical development, including chimeric antigen receptor (CAR) T cells, bispecific T cell engagers (TCE) and antibody drug conjugates (ADC). Idecabtagene vicleucel (ide-cel) is a BCMA CAR T cell therapy that has demonstrated a high frequency of tumor responses, including complete responses, in advanced myeloma patients with low rates of grade 3/4 cytokine release syndrome (CRS) and neurotoxicity (NT) (Raje N, New Engl J Med 2019, Munshi N, N Engl J Med 2021). FDA approval was granted for ide-cel in March 2021. Product and treatment related correlates of durable response and progression have been identified; BCMA antigen escape has been reported, but is rare. bb21217, a next-generation BCMA CAR T cell therapy contains the same CAR construct as ide-cel, but uses ex vivo culture in the presence of a PI3-kinase inhibitor to enrich the final product with memory-like T cells. NEX-T BCMA is another next generation BCMA-targeted CAR T cell therapy that has entered the clinic. T cell engaging bispecific antibodies, while not a cellular therapy, offer another approach to driving T cell mediated BCMA-targeted tumor killing. Taken together these data support the benefit of BCMA targeted, T cell activating immunotherapies for the treatment of advanced myeloma.

4:55 PM

CAR T Cells Targeting GPRC5D and Advances in Dual-Targeting

Speaker

Eric Smith, MD, PhD
Dana-Farber Cancer Institute

BCMA targeted CAR T cell therapy for relapsed/refractory myeloma induces unprecedented response rates in this patient population, however, many patients still relapse. We identified GPRC5D as a novel target for immunotherapy of myeloma and developed CAR T cells directed to this antigen. In mouse models we demonstrated that targeting GPRC5D can rescue BCMA-negative relapse. GPRC5D-targeted CAR T cells stemming from this work are currently under clinical investigation including for relapse post-BCMA CAR T cell therapy. In order to prevent antigen escape driven relapse, we then investigated multiple approaches to dual-targeted CAR T cell therapy.

5:25 PM

Closing Remarks

Speaker

Barbara Knappmeyer, PhD
5:30 PM

Adjourn Day 2

Friday

May 14, 2021

10:30 AM

Welcome Back Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences

Session 9: NK Cells

Session Chairperson
Katharine C. Hsu, MD, PhD Memorial Sloan Kettering Cancer Center
10:35 AM

NK Cell Reactivity and Haplo NK Infusions

Speaker

Katharine C. Hsu, MD, PhD
Memorial Sloan Kettering Cancer Center
11:05 AM

Natural Killer Cells in Solid Cancer

Speaker

Adelheid Cerwenka, PhD
Heidelberg University

Although NK cell-based therapies hold promise in the treatment of leukaemia, immunotherapy of solid cancers is still challenging. In particular, in solid tumors many factors in the hypoxic tumor microenvionment exist that counteract efficient NK cell anti-tumor activity. To obtain a comprehensive understanding of NK cells in solid tumors, we performed single cell RNA sequencing of RMAS-lymphoma infiltrated mouse NK cells compared to blood NK cells. Tumor-infiltrating NK cells were characterized by a signature reminiscent of dysfunctional NK cells. In particular, the transcription factor “Hypoxia Inducible Factor-1a; HIF-1a”, a crucial sensor of hypoxia in the tumor microenvironment, was upregulated in tumor NK versus blood NK cells. Conditional deletion of Hif1a in NK cells resulted in reduced tumor growth, elevated expression of activation markers, effector molecules, and an enriched NF-κB pathway in tumor-infiltrating NK cells. Apart from cytotoxic NK cells, ILCs comprise helper cytokine-producing Innate Lymphoid Cell subsets (ILC 1-3) that are present in many solid tumors. Their role in cancer is still controversial and will be further discussed in the presentation.

11:35 AM

Break

11:45 AM

NK Cell Therapy: Targeting And Off-The-Shelf Strategies

Speaker

Jeffrey Miller, MD
University of Minnesota Medical School
12:15 PM

Neoadjuvant Immune Checkpoint Blockade: A Window into Treatment Response and Primary Resistance

Speaker

Suzanne L. Topalian, MD
Johns Hopkins School of Medicine

Immunotherapies targeting the interaction of programmed death 1 (PD-1) with its ligands, PD-L1 and PD-L2, have revolutionized modern oncology. The PD-1 pathway is a key mediator of local immunosuppression in the tumor microenvironment. In advanced treatment-refractory cancers, drugs blocking this pathway can mediate tumor regression. While anti–PD-(L)1 has demonstrated a broad activity profile and is regarded as a “common denominator” for cancer therapy, many advanced inoperable tumors demonstrate de novo or acquired treatment resistance. One potential solution is to use anti–PD-(L)1 in the neoadjuvant (pre-surgical) setting, when the tumor is potentially “resectable for cure”, to eliminate micrometastatic deposits that could otherwise cause post-surgical relapse. The development of neoadjuvant immunotherapies is based upon immunologic mechanisms and clinical considerations. This treatment approach offers novel clinical endpoints, such as pathologic response assessments. Furthermore, it enables in-depth studies of complete surgical resection specimens to discover biomarkers and reveal new insights into the mechanisms of action of the PD-1 pathway. Hundreds of clinical trials are now underway testing neoadjuvant immunotherapy across a wide variety of cancers.

12:45 PM

Lunch Break

1:15 PM

Virtual Poster Session 2

Session 10: Short Talks

Session Chairperson
Barbara Knappmeyer, PhD, The New York Academy of Sciences
2:00 PM

Discovery of a Naturally Occurring Pluripotent Stem Cell Population in Human Peripheral Blood – Far-reaching Positive Consequences in Adoptive Cell Immunotherapy

Speaker

Vasilis Paspaliaris, PhD
Tithon Biotech

A breakthrough in the field of regenerative medicine and cellular immunotherapeutics came with the introduction of induced pluripotent stem cells (iPSCs).  iPSCs offer an unlimited supply of autologous cells that could be used without the risk of immune rejection. However, problems arose with autologous transplantation of iPSCs and their differentiated end-products, including high cost and excessive manufacturing time, making them clinically impractical to use. Therefore, the solution is to use donor iPSC cell lines to produce allogeneic “off-the-shelf” tissue matching cell products. Although this has reduced the manufacturing time, it is still a relatively expensive exercise that clinically demands immunosuppression. Hypothetically, a naturally occurring PSC found in abundance would have low cost, less manufacturing time, and used autologously, would eliminate immunosuppression protocols. We have discovered, using immunohistochemical analysis, a population of cells in human peripheral blood that are pluripotent, easy to isolate, and abundant. This discovered population of cells range between 1 to 5 million cells per ml of plasma, are relatively small in diameter (<5um), express all four Yamanaka factors (OCT4, SOX2, MYC, KLF4), stain positive for the Kyoto Probe (KP-1), and express Nanog, CD133, CXCR4, SSEA3 and SSEA4. These easily obtainable, naturally occurring PSCs from peripheral blood may have positive implications in generation of tumor-targeting T/NK cells.

2:15 PM

Notch Pathway Activation Drives Immune Evasion in Hepatocellular Carcinoma

Speaker

Katherine E. Lindblad, BS
Icahn School of Medicine at Mount Sinai

Hepatocellular carcinoma (HCC) represents a major health concern, causing over 700,000 deaths annually. Recently, immunotherapies have revolutionized treatment of advanced HCC but, unfortunately, <30% of patients are sensitive, indicating underlying resistance to these immunotherapies. To understand mechanisms of HCC immune evasion, we performed transcriptomic analysis on a collection of immune-escaped murine tumors. We identified an enrichment signature of Notch signaling in immune inflamed tumors that was associated with a specific deficit of CD8+ T cells – a result validated in HCC patient samples. To test the role of Notch in immune escape, we generated a novel mouse model of HCC based on MYC overexpression, activated Notch (MYC;NICD1), and customized expression of tumor antigens (tAg). While expression of tAG in MYC;p53-/- mice led to enhanced survival and immune surveillance compared to MYC;p53-/- mice without tAg, this survival advantage conferred by tAg expression was abrogated in MYC;NICD1 mice, demonstrating that Notch activation drives immune evasion in HCC. Mechanistically, Notch activation led to a reduced number of tumor antigen-specific CD8+ T cells compared to the MYC;p53-/- mice. We are exploring the effects of Notch activation on anti-PD1 response in mice and HCC patients. Together, Notch activation promotes immune escape in HCC and may lead to resistance to anti-PD1 therapy, implicating Notch pathway as a putative biomarker for HCC patient stratification.

Session 11: Tumor Evolution

Session Chairperson
Chris Boshoff, MD, PhD, Pfizer
2:30 PM

Cancer Evolution, Immune Evasion and Metastasis

Speaker

Charles Swanton, PhD
The Francis Crick Institute

Evidence supports complex subclonal relationships in solid tumours, manifested as intratumour heterogeneity. Parallel evolution of subclones, with distinct somatic events occurring in the same gene, signal transduction pathway or protein complex, suggests constraints to tumour evolution that might be therapeutically exploitable. Data from TRACERx, a longitudinal lung cancer evolution study will be presented. Drivers of tumour heterogeneity change during the disease course and contribute to the temporally distinct origins of lung cancer driver events. APOBEC driven mutagenesis appears to be enriched in subclones in multiple tumour types. Oncogene, tumour suppressor gene and drug induced DNA replication stress are found to drive APOBEC mutagenesis. Phylogenetic tracking detects minimal residual disease and clonal evolution of disease from primary to metastatic sites, presenting opportunities for drug development.

On-going chromosomal instability, manifested as Mirrored Subclonal Allelic Imbalance (MSAI) is found to be a major driver of intratumour heterogeneity across cancer types, contributing to parallel evolution and selection. Subclonal driver events, evidence of ongoing selection within subclones, combined with genome instability driving cell-to-cell variation is likely to limit the efficacy of targeted monotherapies, suggesting a need for new approaches to drug development and integration of cancer immunotherapeutic approaches. Multiple adaptive mechanisms to neo-antigen evolution have been found in TRACERx highlighting cancer chromosomal instability driving immune evasion and HLA loss and loss of clonal neo-antigens as well as epigenetic repression of neo-antigens. The clonal neo-antigenic architecture may act as a tumour vulnerability to mitigate resistance and treatment failure.

Session 12: Hematopoietic Cell Transplant

Session Chairperson
Chris Boshoff, MD, PhD, Pfizer
3:00 PM

Unrelated Donor Transplant

Speaker

Bronwen Shaw MD, PhD
Medical College of Wisconsin

Allogeneic transplantation using grafts from matched unrelated donors are the most commonly performed transplant procedures currently. Survival is similar to transplants using a graft from an HLA-identical sibling donor. Although HLA is a major factor in selecting an unrelated donor, several other genetic and non-genetic factors are also of importance. Despite the high number of volunteer unrelated donors listed on international registries not all patients, especially those from racial and ethnic minorities, will have an available donor. Novel strategies are being tested to improve the outcome of transplants using mismatched unrelated donors.

3:30 PM

Haploidentical Transplant

Speaker

Chiara Bonini, MD
Università Vita-Salute San Raffaele, Milan
4:00 PM

Break

4:10 PM

Cord Blood Transplant

Speaker

Juliet N. Barker, MBBS
Memorial Sloan Kettering Cancer Center

Unmanipulated double unit cord blood transplantation (CBT) can be highly efficacious in adults with high-risk hematologic malignancies with comparable progression-free survival (PFS) to that of adult donor allografts in many series. However, as CBT can be associated with delayed hematopoietic recovery, a major focus in the CBT field has been ex vivo expansion. While expansion may be appealing, it has the potential to be logistically challenging. Moreover, the re-frozen/re-thawed T-cell enriched CD34-negative add-back may result in a loss of viable T-cells which could potentially compromise the immune properties of the graft. As an alternative we have investigated unmanipulated double unit CBT in adults with high risk hematologic malignancies using optimized unit selection and transplant practices including a novel intermediate intensity conditioning regimen. This therapy has been associated with very promising outcomes in middle aged adults over 50% of whom have had part or full non-European origins and diagnoses (acute leukemia or other hematologic malignancy) thought to be otherwise incurable. Specifically, both transplant-related mortality and relapse were very low resulting in a 3-year PFS probability of over 75%. Notably, neither the presence of minimal residual disease (MRD) pre-transplant nor engrafting with a highly HLA-mismatched (3-4/8) unit adversely impacted survival supporting the unique immunobiology associated with these transplants. Very promising PFS was observed in AML patients with a high relapse risk according to their diagnosis ELN classification and those with FLT-3 ITD mutations. Transplantation of these cryopreserved, HLA-mismatched, unmanipulated CB grafts after intermediate intensity conditioning should permit more widespread adoption of CBT. It can result in a major extension of allograft access to racial and ethnic minority patients, and those with high risk disease who should not wait to secure an available adult donor or could benefit from the transplantation of a T-replete product. Thus, our findings support further investigation of intermediate intensity double unit CBT in a multi-center setting. Furthermore, we are now using this platform to develop next generation CBT transplants to even further improve transplant outcomes.

Closing Keynote

4:40 PM

Engineering Next Generation Cell Therapies for Enhanced Potency

Speaker

Crystal Mackall, MD
Stanford University
5:25 PM

Closing Remarks

Speaker

Barbara Knappmeyer, PhD
The New York Academy of Sciences
5:30 PM

Conference Ends

Loading...