The Sentinel


Thursday, December 19, 2019

JITC Letter from the Editor - December 2019

pedro-romero_1__1_.jpgDear JITC Readers,

This is the final JITC digest of 2019, and we are ending the year on a historic note with December’s issue containing the most-ever papers published in a single month since the journal’s inception! It has been an exciting year for JITC, and we look forward to what the future holds as the immunotherapy field continues to expand and evolve.

The highlighted papers in this month’s JITC digest truly exemplify some of the most exciting areas of research in our field, spanning preclinical models to human trials and adding new insight into the contribution of the tumor microenvironment to disease progression and immunotherapy resistance as well as the development of novel immunotherapeutic agents.

Be sure to read the Editor Picks below about microenvironment-targeting therapeutics for the reprogramming of myeloid-derived suppressor cells and for the selective depletion of tumor-associated macrophages, gene-edited “off-the-shelf” CAR T cells for the treatment of glioblastoma, preclinical validation for a new checkpoint inhibitor target in ovarian cancer, newly described mechanisms of immunotherapy resistance in melanoma, a deeper understanding of the two types of secondary bone metastases in prostate cancer, and a phase 2 trial describing dendritic cell vaccines for prostate cancer that that induce clinically meaningful immune responses.

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire December 2019 JITC Digest, please click here

Tuesday, December 3, 2019

President's Message - December 2019

Dear Colleagues,
I would like to begin my final President's Message of 2019 by expressing our sincere appreciation to the 4,800 cancer immunotherapy professionals who attended our society's 34th Annual Meeting & Pre-Conference Programs (SITC 2019) in National Harbor last month. The research findings presented at the meeting demonstrated the exciting progress in our field at the bench and the bedside and point us in the direction of finding improved treatments for our patients. The path to a cure for most patients remains difficult, but SITC 2019 again showed that our growing community is capable and committed to achieve this mission.

I'd like to share important highlights of the past year which were possible only because of the outstanding efforts of our members, society leadership and SITC staff. Beyond the clear success that was SITC 2019, our society hosted numerous educational and scientific programs throughout the year, including Advances in Cancer Immunotherapy™ series around North America and workshops on cancer immune responsiveness and adoptive cellular therapies. Additionally, SITC launched new and/or expanded several initiatives to expand opportunities for our members including the Women in Cancer Immunotherapy Network, Cancer Immunotherapy Winter School and the SITC Volunteer Portal. We should all feel proud of one key milestone for this year; SITC eclipsed 3,000 members for the first time in its history – an increase of more than 500 members this year.

In the past 11 months, we also developed bold and ambitious plans for SITC's immediate future. Earlier this year, executive leadership confirmed our society's 2019–21 strategic goals, to include the following:
  • Education and Scientific Exchange: Serve as the leading resource for information and education on cancer immunotherapy 
  • Professional Standards: Set industry standards for the field of cancer immunotherapy in order to position SITC as the authority on immunotherapy of cancer 
  • Global Access and Impact: Advance the science and application of cancer immunotherapy worldwide 
  • Policy and Advocacy: Inform and influence the science and research, regulation, as well as quality of care and quality of access impacted by public policy, ensuring the patient voice is heard and recognized 
  • Science and Research: Challenge the thinking and seek the best research in the exploration and development of tumor immunology and cancer immunotherapy 
  • Leadership Development: Cultivate the next generation of leaders and innovators in tumor immunology and cancer immunotherapy
These six strategic goals are extensions of our historic goals and provide an ambitious agenda and direction for our society's leaders in the next few years. Together, work to achieve each of the goals will bring SITC closer to its ultimate mission, which is to improve cancer patient outcomes by advancing the science, development and application of cancer immunology and immunotherapy. In January, I'll report on plans to fulfill our six strategic goals in 2020.

There is still time in the current year to make progress on one of our most important objectives, leadership development. I invite you to join me in supporting the future of our field through a donation to SITC's Forward Fund. Since 2012, the Forward Fund has awarded more than $3.2 million toward programs, grants and initiatives that support early career scientists through research and education. Please consider making an end-of-year donation to the Forward Fund by Dec. 31, 2019, and your gift will be matched by an anonymous donor.

I would like to thank everyone who contributed toward the success of SITC in 2019. I look forward to the year ahead, working with all of my colleagues, to help SITC advance science and clinical care of cancer patients. Finally, I wanted to share a quick reminder about our online event on Wednesday (tomorrow). SITC will live stream its Advances in Cancer Immunotherapy™ (ACI) program (which is also occurring in-person in Nashville, Tenn.) on Dec. 4, beginning at 4:25 p.m. EST. ACIs are CME-, CPE-, CNE- and MOC-certified programs featuring nearly five hours of engaging cancer immunotherapy education that is free for healthcare professionals in the clinical setting, students and patient advocates. Click here to learn more and register for tomorrow's webcast.

I wish you a happy and safe holiday season.


Mario Sznol, MD
SITC President

Thursday, November 21, 2019

JITC Letter from the Editor - November 2019

pedro-romero_1__1_.jpgDear JITC Readers,

You are receiving this email in the weeks after SITC’s 2019 Annual Meeting and Pre-Conference Programs. This year’s meeting was a smashing success, truly highlighting the broad spectrum of basic science and clinical and translational research in immunotherapy. It is an exciting time for the field, and we are looking forward to possibly seeing some of the data presented at the meeting in upcoming issues of JITC.

Additionally, I am delighted to announce that Dr. Jason Luke, of the University of Pittsburgh Medical Center Hillman Cancer Center, has accepted the role of JITC’s social media editor! Dr. Luke will be managing the journal’s recently launched twitter handle. Be sure to take a moment to follow @JITCancer.

This month’s JITC digest exemplifies the interdisciplinary nature of immunotherapy research, with everything from basic insight into T cell metabolism and immunology to clinical trial results and next-generation sequencing.

“TLR9 acts as a sensor for tumor-released DNA to modulate anti-tumor immunity after chemotherapy” by Tae Hung and colleagues reveals new insight into how platinum-based chemotherapy can act as an immune adjuvant through innate immune danger-sensing pathways.

A review by Bridget P. Keenan et al., “Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response,” describes the delicate balance between protective immunity in the liver and pathological inflammation that may lead to cirrhosis, fibrosis and cancer.

Beatris Mastelic-Gavillet et al. elucidate how adenosine within the tumor microenvironment contributes to disease progression by metabolic suppression of effector T cells. The paper, “Adenosine mediates functional and metabolic suppression of peripheral and tumor-infiltrating CD8+ T cells,” outlines potential biomarkers to monitor future immunotherapies targeting adenosine signaling.

In “Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma,” Indu Ramachandran et al. provide the first evidence for affinity-enhanced receptor engineered SPEAR T cells infiltrating solid tumors—a promising result for the treatment of synovial sarcoma and other malignancies that fail to respond to immune checkpoint blockade.

Finally, Zijun Y. Xu-Monette and colleagues undertake impressive and comprehensive ultra-deep sequencing to identify differential links between somatic hypermutation in immunoglobulin heavy and light chains and clinical outcomes in diffuse large B cell lymphomas in, “Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.”

I hope you enjoy this issue!

With best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire November 2019 JITC Digest, please click here

Monday, November 11, 2019

SITC 2019 Scientific Highlights - Nov. 10

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 10, 2019, sessions of the 34th Annual Meeting.

Role of Sirt2 in T cell activity elucidated

Sirt2 inhibition enhances anti-tumor immunity by promoting T cell metabolism

Abstract O51

Imene Hamaidi, PhD – Moffitt Cancer Center

A possible mechanism for improving anti-tumor immune responses was proposed by Dr. Imene Hamaidi (Moffitt Cancer Center). The role of Sirt2 in immune responses is debated; therefore, this study aimed to elucidate its role in T cell metabolism and function, using murine studies and ex vivo analysis of T cell activity, metabolites, and other immune markers.

In mouse models, Sirt2 deficiency led to a hyper-reactive T cell phenotype, which endowed these mice with an increased capacity to reject engrafted tumors. Similarly, Sirt2-/- T cells exhibited improved anti-cancer activity and hypermetabolism. Upon T cell activation, Sirt2 was observed to interact directly with PFKP, GAPDH, enolase, and aldolase glycolytic pathway enzymes, and modified their activity. Through analysis of tissue samples from clinical trials, patients with increased Sirt2 expression in their TILs were found to have poorer responses to immunotherapy, providing more support to the preclinical studies. Inhibition of Sirt2 pharmacologically increased the effector capacity of human T cells in culture as well. Therefore, the Sirt2 pathway warrants further investigation to improve outcomes to immunotherapy treatments.

Genetic markers for TIL responsiveness identified

The road-map to tumor-infiltrating lymphocyte (TIL) therapy: Understanding genetic alterations for improved patient treatment

Abstract O5

Caitlin Creasy, MS – MD Anderson Cancer Center

Biomarkers for response to TIL therapy in melanoma were presented by Caitlin Creasy, MS (MD Anderson Cancer Center). Pre-treatment tumor tissue samples were analyzed using whole exome (WES) and RNA sequencing and immunohistochemistry to generate correlations with treatment response, progression-free survival, and overall survival.

Overall survival, but not PFS or response, could be predicted from WES results, with a higher neoantigen burden indicative of longer survival. Two genetic mutations were enriched in the overall patient cohort – KCNQ2 and SFTA3. These mutations occurred at a rate higher than that observed in TCGA (1.9 vs 13% and 0.6 vs 6%, respectively), which the authors hypothesized to be a result of the higher-stage cohort in this study relative to the TCGA population. Samples from recurring tumors did not indicate any driver mutations, but changes in the abundance of tumor subclones were observed. From RNAseq, three genes were found to correlate with better outcomes: PDE1C, RTKN, and NGFR; at the same time, ELFN1 was enriched in patients with worse outcomes. Recurrent tumors were found to have markers of a mesenchymal phenotype as well. This study therefore presents possible biomarkers for response, as well as possible pathways of immune escape.

Sunday, November 10, 2019

SITC 2019 Scientific Highlights - Nov. 9

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 9, 2019, sessions of the 34th Annual Meeting.

In vivo tracking of adoptively transferred T cells enabled by PET/CT

Flexible copper-64-nanoparticle-based cell labeling system allows for in vivo tracking of adoptively transferred T-cells by PET/CT

Abstract O1

A flexible system for radiolabeling and tracking adoptive cellular therapies was presented by Hólmfridur R. Halldórsdóttir, MSc (Technical University of Denmark). By labeling T cells in vitro using copper-64 ([64]Cu) micelles, which are self-assembled lipids, the team was able to noninvasively monitor the in vivo biodistribution of these radiolabeled cells over the course of 40 hours using positron emission tomography/computed tomography (PET/CT), and track their response to various therapeutic interventions.

Prior to in vivo imaging, the impact of micelles on T cells was tested. Viability and function of the T cells were not affected by the micelles. Throughout all in vivo studies, there was correspondence between the number of T cells in an organ and the measured radioactivity, indicating the cell tracking technique could provide accurate quantification. Following whole-body irradiation, elevated activity was noted in the thymus compared to non-irradiated mice, which is a well-known homing site for T cells after total body irradiation (4.6±0.1% vs 2.1±0.1% of injected dose, respectively). Tumors were also treated with a sustained release depot of TLR7 agonist, and, following this treatment, a higher accumulation of [64]Cu-labeled T cells was observed in the tumor tissues. This approach may therefore help elucidate the in vivo behavior of adoptive cellular therapies, without compromising their efficacy, which has immense implications for future monitoring of cellular therapies.

HER2-positive cancers may benefit from novel bispecific treatment

A phase 1 dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies

Abstract O82

Sarina Piha-Paul, MD (MD Anderson Cancer Center) presented an investigation of a HER/4-1BB bispecific, known as PRS-343, in patients with HER2-positive cancers. This dose-escalation study has evaluated cohorts from 0.0005 to 8 mg/kg in order to identify the safety profile of PRS-343 and to determine the dose for further studies. Measures of response and biomarkers were among the secondary objectives.

Fifty-three patients with solid tumors have been treated to date, and the minimal active dose was found to be 2.5 mg/kg. At and above this threshold, eighteen patients have been treated and are evaluable. In this patient group, significant expansion of the CD8+ T cell pool was noted after treatment with PRS-343, especially in the tumor microenvironment, in accordance with the proposed mechanism of action for PRS-343. This led to a disease control rate in these patients of 55%, including 2/18 patients confirmed partial response. Higher expansion of CD8+ T cells was found in responding patients over non-responders. The treatment was considered safe, with no serious adverse events or dose-limiting toxicities reported. The investigators are therefore continuing the further investigation of this first-in-class 4-1BB bispecific.

Front-line atezolizumab improves PD-L1+ NSCLC outcomes

IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) monotherapy vs platinum-based chemotherapy (chemo) as first-line (1L) treatment in PD-L1-selected NSCLC

Abstract O81

PD-L1-postive NSCLC patients were treated with either front-line atezolizumab or chemotherapy in the IMpower110 study, presented by Giuseppe Giaccone, MD, PhD (Weill Cornell Medicine). In this study, both squamous and non-squamous NSCLC patients were enrolled, and randomized 1:1 to atezolizumab 1200 mg Q3W or platinum-based chemotherapy for four or six 21-day cycles. As the primary endpoint, overall survival was tested hierarchically by PD-L1 status (highest to lowest expression).

Across both arms of the trial, PD-L1 expression was evenly distributed: 37% of all-comers were TC3/IC3. The majority of patients experienced treatment-related adverse events: 60.5% of atezolizumab patients and 85.2% of chemotherapy patients reported any-grade events, with grade 3-4 in 12.9% and 44.1% as well, respectively. In patients with the highest levels of PD-L1 expression (TC3 or IC3), after a median follow-up of 15.7 months, the overall survival was significantly improved (by 7.1 months) with atezolizumab treatment over chemotherapy (HR=0.595, p=0.0106). The statistical endpoints were not met in the pre-specified next analysis group of TC2/3-IC2/3, however, so further analysis could not be performed for significance at other PD-L1 levels. Front-line atezolizumab may therefore hold promise for further exploration in highly-PD-L1-expressing NSCLC patients, who appear to derive the most benefit in this front-line study.

Microbial colonization linked to colorectal cancer immune responses

Helicobacter hepaticus remodels the tumor immune microenvironment and reduces colorectal tumor burden

Abstract O69

Based on the hypothesis that intestinal microbiota may modulate immune balance, Abigail E. Overacre-Delgoffe, PhD (University of Pittsburgh) presented a preclinical study of microbiome manipulation in colorectal cancer (CRC) models. Colitis-associated CRC was established through AOM-DSS induction, and half of these tumor-bearing mice were colonized with Helicobacter hepaticus (Hhep) after tumor development. Lymphocytes throughout the digestive tract and tumor were analyzed using flow cytometry and confocal microscopy.

Colonization of CRC tumor-bearing mice with Hhep was found to significantly remodel the tumor microenvironment, leading to increased dendritic and Tconv cell infiltration, as well as a decreased Treg presence. This also led to reduction of tumor burden and extension of overall survival for those mice supplemented with Hhep. Using FISH, Hhep was found to colonize not only the normal colonic mucosa, but also infiltrated tumors themselves as well. The authors report that the bacteria also lead to Hhep-specific CD4+ T follicular helper cell (Tfh) infiltration, which may contribute to more efficient anti-tumor immunity, particularly due to the increased number of organized tertiary lymphoid structures in the tumors. Further investigation of the microbiome may in turn provide insight and potential therapeutic mechanisms for improving anti-cancer immune responses.

Biomarkers for immunotherapy responsiveness in sarcomas defined

Immune enrichment and functional T-cell receptor (TCR) frequencies predict response to immune checkpoint blockade (ICB) in selected fusion-associated sarcomas

Abstract O33

Biomarkers of response to immunotherapy for sarcomas were analyzed and presented by Akash Mitra, BS (MD Anderson Cancer Center). Sarcoma patients (alveolar soft part and synovial) were treated with combination durvalumab and tremelimumab, and an in-depth analysis of tumor tissues was performed. Whole-exome, RNA- and TCR-sequencing were conducted to explore correlates with response.

Unlike some other cancer types, tumor mutational burden was not correlated with outcomes in this study. Rather, many immune-related pathways were upregulated in responders, as KEGG pathway analysis indicated higher activity of T cell and B cell response pathways, as well as increases in PD-L1. B cell infiltrates were also more frequent in responding tumors in both pre-treatment and on-treatment biopsies. T cell clonality was inversely correlated with outcomes, with an increased diversity in responders, and a lower maximum productive frequency in responders as well. While further immune deconvolution and BCR sequencing studies are on-going, these genetic and immune signatures may provide greater insight into the immune responsiveness of sarcomas.

Il-35+ B cells play a role in pancreatic cancer progression

IL-35+ B cells regulates anti-tumor immune response in pancreatic cancer

Abstract O47

Bhalchandra Mirlekar, PhD (University of North Carolina - Chapel Hill) presented a study of the immunologic processes that contribute to pancreatic tumor immunotherapy resistance. This involved the use of both spontaneous and orthotopic murine pancreatic tumor models, using a model with B cell-specific genetic loss of IL-35. Combination therapy of IL-35 blockade and immune checkpoint blockade was explored to further elucidate the role of IL-35.

This study uncovered an important role for regulatory B cells in the promotion of pancreatic tumorigenesis. Specifically, this cell population produced IL-35 – a cytokine which has been indicated in the suppression of T cell responses both in autoimmunity and cancer. The study further indicated that only B cell-produced IL-35 was essential for this immunosuppression to occur. When pancreatic tumors from the IL-35 deficient mouse model were treated with anti-PD-1 therapy, regression of normally immunotherapy-resistant tumors was observed. These preclinical studies were also corroborated through analysis of patient pancreatic cancer samples, in which an IL-35+ B cell subset was found, and correlated with dysfunctional T cells. IL-35-targeted therapy may therefore be promising for pancreatic cancer, but the model is still slightly disparate from the actual clinical situation. 

Bispecific anti-PD-1 and CTLA-4 antibody demonstrates promise of lower toxicity

A phase 1 study of AK104, a tetrameric bispecific antibody that targets PD-1 and CTLA-4 in patients with advanced solid tumors

Abstract O30

A dose escalation and expansion study of a PD-1/CTLA-4 bispecific antibody was presented by Ben Markman, MBBS, FRACP (Monash Medical Centre). While combination treatments of individual PD-1 and CTLA-4-targeting antibodies have shown encouraging efficacy, they are also limited by severe toxicities. Therefore, this group hypothesized that the bispecific tetrameric form of AK104 may maintain that efficacy while limiting toxicity due to enhanced tumor specificity. Patients with several solid tumor types were enrolled and dosed between 0.2 and 10 mg/kg Q2W with AK104 with the goal of determining the safety, efficacy, and recommended phase two dose of the treatment.

The bispecific agent was found to have a Kd an order of magnitude better than that of ipilimumab and nivolumab, supporting its improved targeting avidity. Fifty-five patients have been treated with a median of four doses as of data cut-off, with the most at the 6 mg/kg level. Any-grade treatment-related adverse events were reported in 63% of patients, with 11% of patients experiencing a grade 3 reaction, both of which compare favorably to the traditional combination therapy. When patients were treated with doses of at least 2 mg/kg, the overall response rate was 24%, and the disease control rate was 44%. Increases in Ki-67, a proliferation marker, were noted in peripheral CD4+ T cells after treatment with AK104, supporting immune activation. While it remains early to compare the efficacy of AK104 relative to currently-approved combination therapies, the initial safety profile of this agent warrants further investigation.

Immunologic responses noted in vaccine-treated glioblastoma

Phase II trial of therapeutic vaccine consisting of autologous dendritic cells loaded with autologous tumor cell antigens from self-renewing cancer cells in patients with newly diagnosed glioblastoma

Abstract O22

A patient-specific vaccine for glioblastoma patients, AV-GBM-1, was tested in a phase 2 study presented by Daniela Bota, MD, PhD (University of California – Irvine). The technique involved establishment of a short-term cell line from tumor tissue excised at the time of surgery, production of dendritic cells from PBMCs, and development of the vaccine antigens from irradiated tumor cell lysate. Vaccination was performed following completion of standard optimal therapy (surgical resection, radiotherapy, and chemotherapy). The study aimed to achieve a 75% survival rate fifteen months after enrollment, which would represent a 50% increase over survival from current standard therapies.

Thirty-one of the planned 55 patients have begun treatment, with success rates of 46/48 for cell line establishment and 41/42 for development of a successful leukapheresis product. To date, twelve patients completed all eight doses, and five discontinued early due to progression. Immunological responses including Th1, Th2, and Th17 responses were noted in 60% of patients for whom this was measured, indicating promising immune activation with this technique. No notable toxicities have been reported, with all serious adverse events not attributed to the treatment. The study is still ongoing, but, given the encouraging immune activation indications and safety profile so far, the authors are enthusiastic about future results.

Saturday, November 9, 2019

SITC 2019 Scientific Highlights - Nov. 8

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 8, 2019, sessions of the 34th Annual Meeting.

Multiplexed ion beam imaging visualizes gastric irAEs

Gastric toxicity associated with PD-1 blockade therapy revealed by multiplexed ion beam imaging

Abstract O63

A gastric biopsy taken from a patient with nivolumab-associated gastroenteritis was analyzed using multiplexed ion beam imaging (MIBI) by Selena Ferrian, PhD (Stanford University) and colleagues. In order to develop a better understanding of the pathophysiology of this immune-related adverse event, twenty-seven labels were analyzed in a single upper gastric biopsy specimen.

The MIBI analysis visualized markers that were consistent with gastritis and revealed that interferon-gamma was being produced by gastric epithelial cells, rather than by immune cells. The tissue was characterized by a mixed inflammation profile, including both granzyme B-diminished/negative CD8 and FoxP3-diminished/negative CD4 T cells, with the majority of the T cells being CD4+. The investigators defined a set of features found in PD-1-associated gastritis, which included intense immune infiltrate into the lamina propria, interferon-gamma production by glandular epithelial cells, and high Ki67 expression by the epithelial cells as well. This in-depth study of a common immune-related adverse event may thus provide insight into the mechanisms of side effects and guide further immune checkpoint inhibitor development, through elucidating the mechanisms of inflammation and providing future drug targets.

CD27 T cell stimulation combination shows promise

Phase 1 study of an anti-CD27 agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors

Abstract O83

An anti-CD27 antibody, MK-5890, was tested in solid tumor patients in a study presented by Ronnie Shapira-Frommer, MD (Oncology Institute, Sheba Medical Center). Patients received either MK-5890 monotherapy or MK-5890 and pembrolizumab combination therapy, and monotherapy patients were eligible for cross-over upon disease progression. Endpoints of this study included safety and tolerability, with a secondary evaluation of objective response rate.

Forty-four patients were enrolled in the study: 25 received initial MK-5890 monotherapy at doses from 2-700 mg, while 19 were allotted to MK-5890 (200 mg) plus pembrolizumab.  Dose-limiting toxicities were observed in three of the monotherapy patients and one patient with the combination, all of which were related to infusion reactions. Over 90% of patients experienced some level of treatment-related adverse event, and grade 3-4 events were reported in 22.7% of the total population. In these initial cohorts, one patient in each group achieved a partial response. In monotherapy patients that then crossed over to the combination, adverse events were reported by 85%; at the same time, two of these patients exhibited a complete response, and another three partial responses with the median duration of the response not reached. Thus, costimulation of T cells through an anti-CD27 antibody may help improve anti-tumor activity of other therapies with further optimization, and the sequencing of CD27 stimulation appears to play a role in this efficacy.

PD-1-refractory patients may respond to TLR9 agonist

Durable responses in anti-PD-1 refractory melanoma following intratumoral injection of a toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab

Abstract O85

John M. Kirkwood, MD (University of Pittsburgh Medical Center) presented the results of a phase 1b study of pembrolizumab in combination with a TLR9 agonist, CMP-001, in patients with advanced PD-1 refractory melanoma. The majority of patients received combination pembrolizumab and CMP-001 (N=144), while a few were administered CMP-001 alone and allowed to cross-over (N=24). CMP-001, which is a CpG-A TLR9 agonist packaged into a virus-like particle, was intratumorally administered, and safety and efficacy were assessed.

The therapy was tested using a dose escalation/expansion strategy, with initial doses ranging from 1-10 mg CMP-001 (N=44), a first expansion cohort using 5 or 10 mg (N=69), and a second expansion using 10 mg (N=31). CMP-001 was also administered at two concentrations in the first expansion cohort. Overall, the treatment was well-tolerated, with the most common related adverse events being low-grade flu-like symptoms, and six patients discontinuing treatment due to adverse events. Across all cohorts, the ORR was 25%, while, among those receiving the diluted CMP-001 formulation, the ORR was 11%. Responses were noted in non-injected tumors, and, among those responding to the combination therapy, the median duration of response had not yet been reached. Response rates were similar whether a patient received monotherapy or the combination; however, the monotherapy responses were less durable. This combination therapy therefore holds promise to reverse PD-1 resistance in advanced melanomas, potentially through induction of an anti-viral immune reaction that is then able to eradicate tumors.

Prognostic B cell biomarkers identified

B-cell activated by checkpoint blockade immunotherapy and radiation improve overall survival in squamous cell carcinomas

Abstract O12

The importance of B cells in responses to immunotherapy and other cancer therapies was emphasized by Sangwoo Kim, BA (University of California – San Diego). This study evaluated B cell responses and biomarkers in HPV-associated head and neck cancer patient samples as well as in preclinical models. Proteomics arrays and RNA sequencing were employed in human samples (data from the Cancer Genome Atlas), while murine B cell responses were analyzed using BCR sequencing, flow cytometry, and single-cell RNA sequencing after combination treatment with radiotherapy and anti-PD-1 therapy.

The combination therapy in preclinical models was found to impact many aspects of B cell activity: systemic B cell activation, T1 and T2-type B cells, memory cells, plasma cells, and antigen specificity were all altered after the treatments. Specifically, BCR sequencing showed that combination therapy increased the maximum productive frequency and clonality, and also modified the CDR3 length. Increases in B cell germinal center development were also noted through single-cell RNA sequencing, with increasing density resulting from increasing treatment: more cells with a germinal center phenotype were observed with combination treatment over each individual monotherapy. In patient samples, combination therapy was found to increase IgG levels. Traditionally, HPV+ patients have demonstrated enhanced outcomes over their HPV- counterparts; however, this significance was abrogated after CD19 (marker for B cells) was taken into account, indicating that B cells play a major role in responses. For these reasons, the role of B cells in cancer biology and immunotherapy responsiveness merits further investigation and consideration, and development of adequate mouse models will be critical to achieving that goal.

Urinary microbiome linked to BCG response

Variation in the commensal urinary microbiome is associated with response to Bacillus Calmette-Guérin (BCG) immunotherapy in early stage urothelial bladder cancer

Abstract O67

The impact of the urinary microbiome on responses to intravesicular BCG therapy was investigated by Randy Sweis, MD (University of Chicago) and colleagues. Patients receiving BCG therapy experience a similar problem as has been observed with other immunotherapies: up to 50% of patients recur or progress within five years. Therefore, responsiveness to BCG therapy merits further investigation, as in this study. Sterile catheterization was employed to collect urine samples, and these samples were analyzed using 16S rRNA gene sequencing and shotgun sequencing for their microbial contents. Some samples were also analyzed for cytokine levels.

Thirty-one patients were enrolled and followed for a median of 12 months. In that time, 32% of patients recurred after transurethral resection and BCG instillation. Across all patients, the major phyla included Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes; however, distance matrix calculation revealed differences between patients with and without recurrence. Specifically, a higher abundance of Proteobacteria was found in recurring patients (P=0.035), with specific taxa showing even larger differences. At the same time, patients without a recurrence displayed higher levels of Firmicutes (P=0.049). Cytokine analysis in a subset of 13 patients revealed no significant differences between recurring and non-recurring patients. Therefore, the urinary microbiome may indeed have significant impact on the effectiveness of BCG therapy, just as the gut microbiome has been implicated with the effectiveness of other treatments.

CD73 antibody demonstrates immunomodulatory capabilities

Immunobiology and clinical activity of CPI-006, an anti-CD73 antibody with immunomodulating properties in a phase 1/1b trial in advanced cancers

Abstract O40

Phase 1 studies of an anti-CD73 antibody, CPI-006, were presented by Jason Luke, MD, FACP (University of Pittsburgh Medical Center), both as a single agent and in combination with ciforadenant. CPI-006 was administered every three weeks to patients with progressive cancer at doses from 1 to 24 mg/kg, with ciforadenant at a fixed 100 mg orally BID. The immunomodulatory activity of CPI-006 was evaluated through blood analysis of lymphoid subsets, IgH sequencing, and immunohistochemical analysis of tumor biopsies. 

Twenty-four patients received CPI-006 monotherapy, while sixteen received the combination. All-grade adverse events occurred in 75% of patients on both regimens, and grade 3-4 events in less than 17% of patients in both groups. A maximum tolerated dose was not determined. Through tissue occupancy studies, sustained CD73 occupancy in the periphery was found at doses at or above 6 mg/kg, and full tumor occupancy at 18 mg/kg or higher doses. Levels of circulating B and T cells were diminished 30 minutes after infusion, with B cells partially returning three weeks later, and T cell levels fully recovering. In alignment with a humoral immune response, the returning cells had a higher level of memory B cells than before treatment. In patients receiving at least 6 mg/kg CPI-006, tumor reductions were noted in 4/9 patients with RCC, NSCLC, or mCRPC, while no responses were noted in cancers without previous demonstration of sensitivity to these treatments. In addition to its therapeutic potential, the authors hypothesized that treatment with CPI-006 may provide opportunities for identification of novel anti-tumor antibodies due to the induced B cell dynamics.

EGFR-mut NSCLC patients may benefit from neoantigen vaccination

Neoantigen vaccination targeting shared epidermal growth factor receptor (EGFR) mutations induces clinical and immunological responses in non-small cell lung cancer patients

Abstract O18

Gregory A. Lizee, PhD (MD Anderson Cancer Center) presented a phase 1 trial of personalized neoantigen vaccination in non-small cell lung cancer patients. Peptides for vaccination were selected from predicted mutation-encoding neoantigens amongst 508 screened cancer-associated genes. Each of the 24 enrolled patients received at least 12 weekly immunizations in combination with topical imiqimod, and, if EGFR mutation positive (N=16), also had the option to continue on EGFR inhibitors.

Clinical responses were observed in seven patients on the study, all of whom were EGFR mutation-positive. Of these responses, 5/7 displayed T cell responses specific to EGFR neoantigens, and three also had responses to the L858R driver mutation.  The treatment regimen was well tolerated, and no adverse events of Grade 2-5 were observed. For EGFR mutation-positive patients, continuing on EGFR inhibitors was strongly associated with longer overall survival (13.8 vs 7.6 months for continuing vs stopping therapy, P=0.038), indicating a possible synergy between vaccination and EGFR inhibition. Therefore, vaccination may be able to overcome resistance to EGFR inhibitors in NSCLC patients.

Novel CD4+ T cell-DC interactions may lead to increased T cell activity in virally induced cancer

Intratumoral CD163+ DC amplify the type 1 immune response of CD4+CD161+ T cells in HPV16-associated cancers and are associated with better survival

Abstract O44

Several immune cell subtypes were analyzed in HPV16-associated cancers by Chantal Duurland, PhD (Leiden University Medical Center) and colleagues. HPV+ patients have increased survival compared to HPV- patients, thus the role of the immune response to these cancers should be better elucidated. High levels of CD4+CD161+ infiltrating T cells have been found in HPV+ tumors; therefore, the authors used a multi-level approach to understanding the importance of this unique subset of CD4+ T cells in the HPV+ tumor microenvironment. The authors also described a population of CD14-CD33-CD163+ cells, which were identified as dendritic cells (DCs). This subset of DCs was found to associate with strong T cell infiltrates and improved patient survival, similar to CD4+CD161+ T cells. Thus, there was an effort to understand the crosstalk of these two immune subsets in HPV+ disease. Further analyses demonstrated that activated CD163+ DCs generated higher levels of both IL-12 and IL-18 compared to their CD163- counterparts, which in turn induced a type 1 immune response by T cells. Likewise, supplementing patient-derived HPV16-specific CD4+ T cells with IL-12 and IL-18 enhanced their ability to produce interferon-gamma, and this was enhanced compared to the CD4+CD161- T cells. Thus, IL-12 and IL-18 produced by CD163+ DCs can increase stimulation of CD4+CD161+ T cells within the tumor microenvironment, which could ultimately contribute to the improved outcomes of patients with virally induced cancers. This study emphasizes the importance of studying other immune subsets in patient tumors that may ultimately lead to novel immunotherapeutic combinations.

Activated natural killer cell therapy may help Merkel cell patients

Final results from a phase 2 study using off-the-shelf activated natural killer (aNK) cells in combination with N-803, an IL-15 superagonist, in patients with metastatic Merkel cell carcinomaimaging

Abstract O19

Shailender Bhatia, MD (University of Washington) discussed a study of activated natural killer cells (aNK) in patients with Merkel cell carcinoma (MCC). The cellular therapy employed in this trial originated from a rare NK cell lymphoma, and required on-site expansion and activation by irradiation prior to administration. While MCC often responds to PD-1 blockade, nearly half of MCC patients display downregulation of MHC-I or other immune evasion mechanisms, causing them to be refractory to immune checkpoint therapy. Therefore, this group explored the use of aNK cell therapy in this population, as this treatment option is effective even in the absence of MHC-I.

Seven patients were treated – three with aNK therapy alone, and another four with aNK and N-803 (an IL-15 superagonist) combination therapy. The therapy was well-tolerated, without any treatment-related adverse events over grade 2. Two of the seven patients experienced objective responses. One patient, refractory to pembrolizumab, achieved a complete response on aNK monotherapy; however, after six months, the patient then relapsed. Re-challenge with pembrolizumab after this relapse resulted in a complete response ongoing at 36 months. These promising initial findings have led the investigators to begin other trials related to the aNK therapy as well, without the requirement for on-site processing to aid in the treatment’s feasibility.

Single-cell RNAseq links T follicular helper cells to improved outcomes in HNSCC

Transcriptional dissection reveals antitumor role of T follicular helper cells in head and neck cancer

Abstract O42

Anthony R. Cillo, PhD (University of Pittsburgh) and colleagues performed single-cell RNAseq analysis of more than 130,000 CD45+ cells sorted from PBMCs and TILs of immunotherapy-naive HNSCC patients both with and without HPV infection, as well as samples from healthy donors.

A unique T follicular helper (TFH)-like gene expression signature was observed in CD4+ Tconv cells in TILs from HPV positive patients whereas a mainly effector-memory signature was detected in TILs from HPV- patients. Immunofluorescence analysis showed tertiary lymphoid structures in HPV+ patient samples, further implicating a role for TFH in HNSCC. Analysis of patient data from the cancer genome atlas revealed that a high TFH signature was associated with extended progression-free survival, even after an multivariate analysis controlling for 9 covariates (hazard ratio=0.041, p=0.02). The increased understanding of the immune microenvironment of HNSCC from this study may provide guidance for development of future immunotherapies.

SITC 2019 Scientific Highlights - Nov. 7

The Society for Immunotherapy of Cancer (SITC) is pleased to present scientific highlights from the Nov. 7, 2019, sessions of the 34th Annual Meeting.

In-depth imaging of AML shows wide heterogeneity

Mapping the spatial architecture of acute myeloid leukemia in the bone marrow microenvironment by multiplexed ion beam imaging

Abstract O79

Inter- and intratumor heterogeneity potentially play a role in treatment failure and the outgrowth of drug-resistant clones in acute myeloid leukemia (AML). To better understand the variability in the bone marrow microenvironment in patients with AML, Xavier Rovira-Clave, PhD (Stanford University) presented a detailed analysis of tissue microarrays prepared from FFPE samples from 119 individuals. Using high-resolution multiplexed ion beam imaging (MIBI), a technology that allows the simultaneous characterization of numerous parameters with a 5-log dynamic range, the spatial distribution of 40 functional and phenotypic markers were mapped. A range of 500 to 2500 cells were imaged per patient in the gender-balanced cohort, totaling more than 100,000 cells analyzed in the study. Profound inter-tumor heterogeneity was observed between samples, as well as intratumor heterogeneity in terms of the levels of proliferation markers, AML-related markers and other cellular proteins. Such high-resolution mapping of the bone marrow architecture adds insight into the intra- and inter-tumor heterogeneity in AML, and this emerging technology could potentially be used to test if cell specific cell subtype co-occurrence contributes to driving disease progression.

CD3/CD33 bispecific shows promise in phase I

AMV564, a novel bivalent, bispecific T-cell engager, targets myeloid-derived suppressor cells

Abstract O71

Victoria Smith, PhD (Amphivena Therapeutics, Inc) reported evidence that treatment with AMV564, a bispecific antibody that engages CD3 and CD33, is well-tolerated and selectively depletes myeloid-derived suppressor cells (MDSCs) in patients with acute myeloid leukemia. No dose-limiting toxicities were reported in ongoing phase 1 clinical trials, and complete responses were observed in some patients. AMV564 treatment led to rapid depletion of both monocytic and granulocytic MDSCs as well as CD4+ and CD8+ T cell activation with no impact on circulating neutrophil or monocyte populations. However, MDSCs exhibited dynamic responses to T cell activation, and rapid rebounds were observed when AMV564 was discontinued, leading to a modified dosing strategy. The ability of AMV564 to deplete MDSCs while activating cytotoxic and helper T cells may synergize with existing immunotherapies and the results indicate AMV564 may be beneficial in the treatment of solid tumors, where MDSCs are associated with reduced responses to immunotherapy and poor outcomes.

Off-the-shelf BCMA CAR therapy shown feasible in preclinical and translational studies

P-BCMA-ALLO1 – a nonviral, allogenic anti-BCMA CAR T therapy with potent anti-tumor function for the treatment of multiple myeloma

Abstract O7

An “off-the-shelf” BCMA-targeting CAR T cell product candidate described by Maximilian Richter, PhD (Poseida Therapeutics, San Diego, CA) showed promising anti-myeloma activity in vitro and durable responses in xenograft mouse models. Using the nonviral PiggyBac DNA Modification System to deliver the CAR transgene along with a proprietary “booster molecule” in combination with the high-fidelity Cas-CLOVER Site-Specific Gene Editing System to knock out expression of the endogenous T cell receptor and MCH, Richter and colleagues demonstrated efficient manufacturing of the allogeneic CAR T therapy P-BCMA-ALLO1 from healthy donor cells, with final product composition greater than 95% CAR+, greater than 99.5% TCR-KO and a high percentage of T stem cell memory cells (CD45RA+, CD62L+), which are able to implement effective anti-tumor immunity. The robust, non-viral gene-modification process was compatible with the majority of healthy donors, and yielded hundreds of doses per manufacturing run. In NGS xenograft mice implanted with RPMI-8226, an aggressive human multiple myeloma-derived tumor model, P-BCMA-ALLO1 treatment led to sustained reduction of tumor burden below the limit of detection by caliper within roughly 2 weeks, whereas control animals succumbed to disease within 5-7 weeks. The preclinical evidence sets the groundwork for advancement of P-BCMA-ALLO1 into clinical studies for the treatment of multiple myeloma while providing a promising technological framework for the development of allogeneic CAR T products targeting additional antigens.

CRS management strategy does not impact CAR efficacy

Myeloid cell-targeted miR-146a mimic alleviates NF-kappaB-driven cytokine storm without interfering with CD19-specific CAR T cell activity against B cell lymphoma

Abstract O61

Cytokine Release Syndrome, a serious adverse event associated with chimeric antigen receptor (CAR) T cell therapies, is known to arise due to the NF- kappaB-driven release of IL-1 and IL-6 from monocytes. Yu-Lin Su, PhD (City of Hope, Duarte, CA) presented studies of C-miR146a, a myeloid cell targeted NF-kappaB inhibitor consisting of a chemically-modified miR146a mimic oligonucleotide tethered to a scavenger receptor/Toll-like receptor 9 (TLR9) ligand. In vitro, the inhibitor, C-miR146a, was rapidly internalized and delivered to cytoplasm of target myeloid cells including macrophages and myeloid leukemia cells where it reduced protein levels of classic miR-146a targets, IRAK1 and TRAF6, thus blocking NF-kappaB activation. Additionally, C-miR146a treatment reduced CD-19 CAR T cell-induced IL-1 and IL-6 production in human monocytes, in vitro. In a mouse xenograft model of B cell lymphoma, repeated systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent CRS without impeding the on-target therapeutic effects of CAR T-cells against lymphoma cells. In two different mouse models of del(5q) leukemia, repetitive injection of C-miR146a led to suppression of tumor growth without significant toxicities. The study provides an outline for the development of miRNA therapeutics to augment therapeutic efficacy of CAR T cells in acute myeloid leukemia as well as for the prevention of cytokine release syndrome.

Tuesday, November 5, 2019

President's Message - November 2019

Dear Colleagues,

This week we anticipate welcoming 5,000 scientists, clinicians, industry professionals and others to the Society for Immunotherapy of Cancer’s 34th Annual Meeting & Pre-Conference Programs (SITC 2019) in National Harbor, Md. Our society and our Annual Meeting have been growing rapidly for two key reasons; the unprecedented success of cancer immunotherapy in the clinic, and the hope and expectations we all share that continued research in our field will produce more effective treatments for patients. From the small group that formed the society in the early 1980s, we have now grown to almost 3,000 members. By working together to promote research, education and the careers of our members, we can achieve the primary goal of the Society, which is to improve the lives of cancer patients.

At SITC 2019, we will once again gather together to hear and discuss the latest research and to develop new ideas and collaborations for the lab and clinic. The depth and quality of cancer immunotherapy research at our upcoming meeting is evident in the nearly 1,000 abstracts submitted to SITC 2019, as well as the SITC 2019 late-breaking abstract titles. The meeting organizers have worked diligently to bring the best science to the meeting, and to make the meeting a forum for discussion of the latest clinical advances. Along these lines, I’m excited to announce that we’ve added a new session to the 34th Annual Meeting programming on Saturday, Nov. 9, at 7 a.m., bringing together world experts to discuss the clinical implications of the most recent phase III immunotherapy trials in non-small cell lung cancer (more details are below). We hope you’ll join us!

On behalf of the society, I want to thank everyone who chose to bring their latest data to SITC 2019; I look forward to seeing your presentations this week in National Harbor and the engaging discussions that will follow.

Finally, I would also like to emphasize how much we value and appreciate the commitment of veteran and new members to our society. As we prepare to travel to National Harbor, I’d like to remind you that the 2019 SITC member dues cycle closes with the opening of our Annual Meeting & Pre-Conference Programs. Those who join SITC or renew their membership while attending SITC 2019 will receive the value of nearly 14 months of SITC membership. As a small token of appreciation, SITC members who renew their membership in National Harbor will also receive an exclusive SITC backpack and individuals who become a new SITC member will receive a society-branded water bottle. More information will be available when you arrive at SITC 2019 and receive your registration materials.

I look forward to seeing you all this week in National Harbor!


Mario Sznol, MD
SITC President