The Sentinel

THE OFFICIAL BLOG OF THE SOCIETY FOR IMMUNOTHERAPY OF CANCER (SITC).

Saturday, November 13, 2021

SITC AMPCP 2021 Scientific Highlights – Saturday 11/13/21

 Off-the-shelf CAR NK cells potently control multiple tumor types

(117) FT536 Path to IND: Ubiquitous targeting of solid tumors with an off-the-shelf, first-of-kind MICA/B-specific CAR-ink cellular immunotherapy

Bryan Hancock, PhD (Fate Therapeutics) previewed the preclinical studies supporting the investigational new drug application for FT536, a CAR NK cell product derived from an inducible pluripotent stem-cell line engineered for enhanced effector cell functionality, persistence, and multi-antigen targeting capabilities through CD16-mediated antibody dependent cellular cytotoxicity (ADCC). FT536 carries a CAR targeting the pan-tumor associated antigens MICA and MICB (MICA/B) and the product can be consistently and uniformly produced as well as cryopreserved at clinical scale. Potent and persistent antigen-specific cytotoxicty was demonstrated against an array of solid and hematological tumor lines. Activity of FT536 was further augmented when combined with chemotherapies and/or radiation that induced surface MICA/B expression. Multi-targeting through the CAR and CD16-mediated ADCC was also demonstrated when FT536 was combined with trastuzumab or cetuximab for HER2- or EGFR-expressing tumors, respectively. In xenograft models, directly thawed frozen FT536 significantly slowed tumor growth, which was further enhanced when infused in combination with the monoclonal antibodies. Sustained persistence of FT536 for 33 days post-infusion were also seen in a murine model of lung adenocarcinoma. These preclinical findings support further development of FT536 as a universal adoptive cell therapy.

 

 

Anti-CD47 shrinks breast cancer brain metastases

(270) Anti-CD47 immunotherapy as a therapeutic strategy for the treatment of breast cancer brain metastasis

Jessica D. Mackert, PhD (Wake Forest University) described preclinical data supporting CD47 as a target for the treatment of brain metastases in triple-negative breast cancer (TNBC). The “don’t eat me signal” CD47 is a pleitropic surface marker expressed on numerous cell types that inhibits myeloid cell phagocytic activity through binding SIRPalpha as well as an antagonizes T cell function mediated by interaction with matricellular protein Thrombospondin-1. Patient biopsies revealed an 89% increase in CD47 expression by immunohistochemistry in metastatic brain TNBC tumors compared to primary lesions. In mice bearing brain metastatic 4T1br3 tumors, anti-CD47 treatment shrank tumors by roughly 50% compared to controls, which accompanied by a 5-fold increase in expression of F4/80 macrophage markers in the tumors. A total of 318 differentially expressed genes were associated with anti-CD47 treatment, with enrichment for reduced signatures of extracellular matrix remodeling and upregluation of pathways involved in tertiary lymphoid structure formation. Knockout of CD47 led to 60% increased survival and 89% decreased metastatic brain lesions in 4T1-bearing mice compared to controls. This preclinical data supports CD47 as a potential target for the immunotherapeutic treatment of brain metastases.

 

 

DNA vaccine plus pembrolizumab for metastatic prostate cancer

(350) Phase II trial of a DNA vaccine with pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC)

Douglas G. McNeel, MD, PhD (Carbone Cancer Center, University of Wisconsin) presented the final analyses from Arms 3 and 4 of a phase I/II study evaluating the pTVG-HP prostatic acid phosphatase (PAP) DNA vaccine in combination with pembrolizumab for metastatic castrate-resistant prostate cancer (mCRPC). In arm 3, the PAP DNA vaccine was given every 3 weeks (with pembrolizumab every 3 weeks) and in Arm 2, the vaccine was given every 2 weeks (with pembrolizumab every 4 weeks). The median time to progression (TTP) at the time of abstract preparation was 5.3 months for Arm 3 and 8.0 months for Arm 4. Updated 6-month disease control rates presented at the meeting were 10% and 45% of patients in Arms 3 and 4, respectively. Treatment-related adverse events ≥ grade 2 occurred at a rate of 42% across arms, and development of an immune-related adverse event was associated with prolonged TTP. Persistent increases in serum levels of interferon gamma and granzyme B were observed in both Arms (6/20 patients in Arm 4 and 2/20 patients in Arm B). These data suggest that the generation of tumor-antigen-specific T cells through vaccination may help overcome primary resistance to anti-PD-1 monotherapy in prostate cancer.   

 

 

Ibrutinib enhances CLL CAR-T cell therapy 

(449) Concurrent ibrutinib enhances T cell function in patients with chronic lymphocytic leukemia (CLL) treated with lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T cell therapy

Jerill Thorpe, MS (Bristol Myers Squibb) described translational data supporting potential synergy between Bruton tyrosine kinase inhibitors (BTKi) and CAR T cell therapy in patients with chronic lymphocytic leukemia (CLL). Using a novel low-input RNA-seq method, CAR-positive and endogenous T cells were isolated from the patients treated in the TRANSCEND CLL 004 study, which evaluated the CD19-directed CAR T cell product lisocabtagene maraleucel (liso-cel) given with the BTKi ibrutinib (n = 19) or as monotherapy (n = 16). At 1 and 2 months post-liso-cel infusion, both populations of cells in the combination ibrutinib plus liso-cel group demonstrated positive enrichment for expression of cell proliferation genes and negative enrichment for expression of inflammation-associated genes compared to what was seen with monotherapy, though the extent was lesser in the endogenous lymphocytes. Increased CAR+ T cell expansion, reduced serum IL-6, and increased and sustained CLL ibrutinib gene expression score—which has previously been correlated with higher rates of undetectable minimal residual disease and longer progression-free survival—was also seen in the combination group. The expression of T cell exhaustion genes was reduced in CAR-positive cells from the combination group, which was associated with improved progression-free survival. These findings suggest that the addition of ibrutinib to CAR T cell therapy for CLL.  

 

 

TIL therapy plus pembrolizumab leads to durable responses

(492) Phase 2 efficacy and safety of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers

David O’Malley, MD (Ohio State University) reported early efficacy and safety results from two ongoing multicenter phase II clinical trials investigating autologous tumor-infiltrating lymphocyte (TIL) therapy combined with pembrolizumab for the treatment of head and neck squamous cell carcinoma (HNSCC), melanoma, and cervical cancer. Patients’ tumors were first resected for TIL isolation and manufacturing, followed by one dose of pembrolizumab, lymphodepletion, TIL infusion intravenous IL-2, and then continued pembrolizumab for ≤ 24 months. All enrolled patients had high tumor burdens. At median follow-up of 9.7 months, the objective response rates in the full analysis set presented at the meeting were 60%, 39%, and 57%, for patients with melanoma, HNSCC, and cervical cancer, respectively. Almost all efficacy-evaluable patients achieved a reduction in tumor burden. Ongoing durable responses at data cutoff were observed in 10 of 17 patients with objective tumor response. Reporting tolerable safety results thus far, the authors advocate for further investigation of this combination immunotherapy strategy as an early line of therapy option for patients with advanced solid tumors.

 

Intact lymph nodes are essential for checkpoint inhibitor efficacy

(601) Sequencing Immunotherapy before Lymphatic Ablation Unleashes cdc1-Dependent Antitumor Immunity in HNSCC

Robert Saddawi-Konefka, MD, PhD (UC San Diego) presented preclinical evidence to determine the best sequence of therapies for head and neck squamous cell carcinoma (HNSCC) based on spatially distinct patterns of immune responses in cervical lymphatic basins. In murine models of neck dissection (ND) to remove orthotopic tobacco-signature HNSCC tumors, enrichment for conventional type I dendritic cells (cDC1)and type I interferon signaling was observed within the resected lymphatics. After ND, the tumor microenvironment was observed to be largely immunosuppressed, suggesting a loss of effector function after curative-intent surgery. Specifically, ND resulted in loss of tumor-specific CD8+ T cells and increases in myeloid suppressive cells. Supporting this, poor immune responses were observed with immune checkpoint inhibitors (ICIs) following cervical lymphatic ablation. ICIs given neoadjuvantly, however, resulted in a systemic distribution of memory anti-tumor T cells, lymph node accumulation of cDC1, and complete responses in tumors. Interestingly, administration of ICIs prior to surgery was also associated with reduced occurrence of occult nodal metastases at late time points (1 week after the last ICI dose), but not when surgery was performed at an early time point (1 day after the last ICI dose) providing preclinical evidence for the importance of the draining lymph node in generation and maintenance of prolonged anti-tumor responses.

 

 

Safety data support COVID-19 vaccination for checkpoint inhibitor-treated patients

(625) COVID-19 vaccination in patients with renal cancer or melanoma receiving immune checkpoint inhibitors

Hannah E. Dzimitrowicz, MD (Duke University) described no increased incidence of immune-related adverse events nor severe side effects associated with COVID-19 vaccination for patients receiving checkpoint inhibitors—a population that was excluded from the registration trials leading to Food and Drug Administration (FDA) approval. Retrospective data on balanced cohorts of patients with renal cell carcinoma and melanoma undergoing checkpoint blockade therapy who received one dose of an FDA-approved vaccine was presented. Half of the patients were being treated with anti-PD-1 monotherapy at the time of vaccination. Among the 40% of patients being treated with immunotherapy combinations, 10% of patients were receiving anti-PD-1 plus anti-CTLA-4 and 28% had a regimen that included anti-PD-1 plus a tyrosine kinase inhibitor. Higher rates of symptoms secondary to vaccination were reported by the ICI-treated patients, including fever, chills, arm pain, myalgias, lymphadenopathy, headache, and diarrhea, likely related to more frequent follow-up compared to the control group. The rates of new or worsening immune-related adverse events after vaccination was no higher than predicted by expected historical ICI-associated toxicity incidence rates. Only 12% of patients required a hold of checkpoint inhibitor therapy, steroids, or hospitalization due to immune-related toxicity. Some patients did develop COVID-19 after partial vaccination. Further studies with larger cohorts of patients are needed to assess efficacy of the approved COVID-19 vaccines in ICI-treated patients, yet these data indicate vaccination is safe for this vulnerable population.

 

STING agonism alters stroma to turn cold tumors hot

(758) High-potency synthetic STING agonists rewire the myeloid stroma in the tumour microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic ductal adenocarcinoma

Akash R. Boda, MS (University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences) provided the first detailed mechanistic characterization of how synthetic agonists of the Stimulator of Interferon Genes (STING) adaptor protein perturb the myeloid stroma toward proinflammatory phenotypes. Multi-omics profiling on M2 macrophages and myeloid-derived suppressor cells of both human and murine origin revealed that exposure to synthetic cyclic dinucleotides (high-potency agonists of STING) rewired these cell populations via inhibition of c-Myc signaling, alteration of energy metabolism away from fatty acid oxidation in favor of oxidative phosphorylation, and antagonism of proliferation. In orthotopic mouse models of KRAS-driven pancreatic ductal adenocarcinoma (PDAC)an immunologically cold tumor—intratumoral injection of synthetic cyclic dinucleotides concomitant with checkpoint blockade led to enhanced T and NK cell infiltration along with improved disease control. Multiparametric flow cytometry analysis of tumors from mice treated with the combination of STING agonists and checkpoint inhibitors confirmed that remodeling of the myeloid stroma toward proinflammatory phenotypes with accompanying enhancements in T cell function were both associated with therapeutic benefit. The study not only offers new insight into the mechanisms by which cyclic dinucleotides act as immune adjuvants for anti-tumor responses, but also highlight the potential of these compounds to reverse primary resistance to checkpoint blockade in immunologically cold tumors such as PDAC.

 

 

Skin toxicity predicts improved survival with checkpoint blockade

(814) Cutaneous Immune-related Adverse Events are Protective of Mortality in Patients Treated with anti-PD1 and anti-PDL1 therapy in a multi-institutional cohort study

Yevgeniy Semenov, MD (Massachusetts General Hospital/Harvard Medical School) presented a retrospective study that included 7,008 patients who developed cutaneous immune-related adverse events (cirAEs) within 6 months of treatment initiation of anti-PD-(L)1 therapy as well as 7,008 control-matched patients that did not experience skin toxicity. Landmark analyses at 6 months showed statistically significant improvement in overall survival among the patients who developed any cirAE as well as individual toxicities including nonspecific rashes, pruritus, drug eruption, and xerosis. Other cirAE morphologies also demonstrated a trend toward improved survival without reaching statistical significance. The onset of a cirAE within 3 months or 9 months of first dose of PD-(L)1 inhibitor was similarly associated with a reduced risk of death (HR 0.759, p < 0.0001 for a 3 month landmark time; HR 0.84, p < 0.0001 for a 9 months landmark time). These data suggest that many dermatologic irAEs may be predictive of survival benefit from anti-PD(L)1 therapy.  

 

 

Combination pembrolizumab plus oncolytic virus improves CR rates for NMIBC

(955) CORE1: Phase 2, Single Arm Study of CG0070 Combined with Pembrolizumab in Patients with Non Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG)

Roger Li, MD (Moffitt Cancer Center) reported early data from a phase II study of an intravesical oncolytic virus combined with systemic pembrolizumab therapy for the treatment of BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). CG0070 is a GM-CSF-expressing adenovirus engineered to harbor the transcription factor E2F, which allows for preferential replication in tumor cells with defects in the tumor suppressor protein retinoblastoma—resulting in lysis and immunogenic cell death. Encouraging CR rates have been reported previously in separate studies of CG0070 and pembrolizumab monotherapies for NMIBC, and this is the first trial assessing a combination approach. The primary study endpoint is CR at 12 months, with secondary endpoints of CR at any time, progression-free survival, duration of response, cystectomy-free survival, and safety. At the time of abstract submission, 5 out of 5 assessed patients had achieved CR at 3 months, and there were no grade ≥ 3 adverse events reported. Updated data presented at the meeting confirmed the 100% CR rate at 3 months in 2 additional patients and demonstrated ongoing CRs at 6 and 9 months for the 2 and 6 patients for whom longer follow-up was available. These preliminary data support further evaluation of CG0070 plus pembrolizumab, a combination that has demonstrated unprecedented CR rates, has been well-tolerated to date and may exhibit synergistic anti-tumor effects.

 

 

SITC AMPCP 2021 Scientific Highlights – Friday 11/12/21

Engineered myeloid cells make the microenvironment more favorable 

209 Genetically Engineered Myeloid Cells (GEMys) as a Platform to Enhance Antitumor Immunity 

Sabina Kaczanowska, PhD (National Cancer Institute) presented evidence that engineered IL-12-expressing myeloid cells home to tumors and modulate effector cell functions in the microenvironment. Previous work by this group has demonstrated that bone marrow-derived myeloid cells play a central role in establishing the pre-metastatic niche. In murine models of lung metastases, treatment with IL-12-expressing myeloid cells was associated with robust interferon gamma responses, elevated antigen presentation machinery, and high infiltrating T and NK cells expressing effector markers. Tumor growth was blunted in mice infused with engineered cells, resulting in fewer metastases, and prolonged survival compared to controls. When combined with chemotherapy pre-conditioning, treatment not only was associated with complete rejection of established tumors but also resistance to rechallenge. Translation of these findings into human patients could open the door for myeloid-targeting strategies to prevent metastasis in advanced cancer.

 

Combination improves survival for immunologically cold endometrial cancer 

(354) Lenvatinib and pembrolizumab in advanced endometrial carcinoma (EC): long-term efficacy and safety update from a phase 1b/2 study

Vicky Makker, MD (Memorial-Sloan Kettering Cancer Center) delivered an update from a phase Ib/II study of the multikinase inhibitor lenvatinib plus the pembrolizumab for metastatic, pre-treated endometrial carcinoma. The trial enrolled  108 patients, 94 of whom had confirmed microsatellite stable (MSS)/mismatch repair proficient (pMMR) disease and 11 with documented microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) tumors. At data cutoff on January 10, 2019 with a median follow-up of 18.7 months, the objective response rate (ORR) was 38.9%, median progression-free survival (PFS) was 7.4 months, and median overall survival (OS) was 16.7 months. Now, with a median follow up of 34.7 months, the updated ORR is 38.3% (including an 8.3% complete response rate) and 63.6% for MSHI-H/dMMR tumors. Median PFS remained consistent with the first analysis at 7.4 months (7.4 and 26.4 months for MSS/pMMR and MSI-H/dMMR tumors, respectively), and the updated median OS is 17.7 months (17.2 months and not reached for MSS/pMMR and MSI-H/dMMR tumors, respectively). No new safety signals were detected. With continued follow-up, this phase Ib/II study that included primarily patients with MSS/pMMR advanced endometrial carcinoma continues to demonstrate efficacy not previously achieved with pembrolizumab monotherapy in this “immunologically cold” tumor. A phase III trial of lenvatinib plus pembrolizumab compared to chemotherapy is ongoing.

 

Novel drug traffics non-conventional T to cells tumors

(503) Clinical Activity of ICT01, an anti-BTN3A-Targeted, γ9δ2-Activating mAb, Alone and in Combination with Pembrolizumab in Patients with Advanced/Refractory Solid Tumors: EVICTION Trial

Martin Wermke, MD (Technical University, Dresden) described clinical evidence that treatment with an antibody targeting butyrophilin-3A (ICT01) leads to tumor infiltration by the non-conventional cytotoxic γ9δ2 T cell subset.  In the ongoing phase I/IIa EVICTION trial, dose-escalation of ICT01 (20µg to 200mg) has been completed as well as three dose cohorts of ICT01 (700µg, 2mg, or 7 mg) plus pembrolizumab. Blood samples were collected and tumors were biopsied for analysis at baseline and on day 28. No dose-limiting toxicities were observed in any of the completed cohorts. Treatment mediated  trafficking of γ9δ2 T cells out of circulation with, associated intra-tumoral increases in total γδ (3 to 34-fold), CD3+ (3 to 55-fold) and CD8+ T cells (1.3 to 66-fold). Stable disease as measured by RECISTv1.1 was observed in 6 of 19 evaluable patients in the dose-escalation cohort and 5 of 8 evaluable patients in the combination cohort. Furthermore, 2 of 8 patients in the combination cohort had a PR. One patient notably had shrinkage of an intracranial metastatic melanoma lesion in a patient refractory to prior ipilimumab plus nivolumab after initial pseudoprogression. These preliminary data suggest that ICT01 effectively mobilizes γ9δ2 T cells to tumors and clinical benefit may be enhanced when combined with pembrolizumab.

 

Autoantigen driving immune-related myocarditis identified

(805) Clonal, activated CD8+ T cells recognizing cardiac alpha-myosin drive immune checkpoint inhibitor associated myocarditis in mice

Margaret Axelrod, BS (Vanderbilt University) presented a new murine model of checkpoint inhibitor-induced myocarditis that led to the identification cardiac alpha-myosin as a key autoantigen driving this rare but often deadly toxicity. Mice with homozygous knockouts of the gene encoding PD-1 and heterozygous deletion of the CTLA-4 encoding locus spontaneously develop fatal myocarditis that recapitulates the clinical features of human immune-mediated toxicity. Depletion of either CD4+ or CD8+ T cells rescued survival in mice, but single cell RNA/T cell receptor sequencing identified CD8+ T cells as the dominant population in the cardiac immune infiltrate. Reporter assays confirmed that the most clonally expanded receptors recognized epitopes of alpha-myosin. This study is the first identification of a candidate autoantigen in checkpoint blockade-associated-myocarditis and efforts are underway to determine if human T cell receptors isolated and sequenced from patient samples also recognize similar epitopes.

 

Gut microbiota contribute  to colorectal cancer immune contexture

(839) Microbiota-specific T follicular helper cells drive tertiary lymphoid structure formation and anti-tumor immunity in colorectal cancer

Abigail Overacre-Delgoffe, PhD (University of Pittsburgh) discovered  that T cells specific to individual constituents of the gut microbiota are involved in anti-tumor immunity. In a carcinogen-induced model of colorectal cancer, mice colonized by the enterohepatic pathogen Helicobacter hepaticus was associated with decreased tumor burden and prolonged survival compared to uncolonized controls. Tumors isolated from H. hepaticus-colonized animals displayed mature peri- or intra-tumoral tertiary lymphoid structures, which were associated with high levels of infiltration of cytotoxic T and NK cells. Depletion of CD8+ T cells did not attenuate the anti-tumor effects of colonization with H. hepaticus, however, CD4+ T follicular helper cells were necessary and sufficient to slow tumor growth. These data reveal unappreciated roles for the microbiota as well as CD4+ T follicular helper cells in modulating the tumor immune microenvironment, possibly paving the way toward new therapeutic targets.

 

Sex differences shape the tumor microenvironment in pancreatic cancer

(885) Targeting FPR2 as a novel approach for immunotherapy in pancreatic cancer female patients – Studies of sexual immune dimorphism in the tumor microenvironment

Dhifaf Sarhan, PhD (Karolinska Institutet) identified a sex-specific mechanism of myeloid-cell driven immune exhaustion that contributes to the immunologically cold phenotype of pancreatic cancer. Interrogation of murine and human transcriptomic data showed elevated expression of G-coupled protein receptor formyl peptide receptor 2 (FPR2) in pancreatic tumor samples compared to healthy tissues. FPR2 was also higher in women than in men. FPR2-expressing myeloid cells in tumors were associated with distinct sex-specific immunophenotypes for both mice and humans, with an immune-excluded phenotype predominating in females versus an immune-ignored phenotype in males. In vitro, myeloid cells treated with FPR2 agonist induced TIM3 and PD-1 on T cells isolated from women but not from men. Knockout of FPR2 slowed subcutaneously injected pancreatic tumor growth to a significantly greater extent in female mice compared to males. Data from human patients with pancreatic cancer and other gastric malignancies confirmed an association between FRP2 expression and poor survival outcomes in women only. This study opens the door to sex-specific personalized immunotherapy approaches and reveals myeloid FPR2 as a new microenvironmental mediator involved in T cell exhaustion in women.

 

First human experience with CAR-transduced macrophages reported

(951) A Phase 1 first in human study of adenovirally transduced anti-HER2 CAR Macrophages in subjects with HER2 overexpressing solid tumors: preliminary safety, pharmacokinetics, and TME reprogramming data

Kim Reiss, MD (University of Pennsylvania) reported the first-in-human experience with adoptive therapy with CAR-transduced macrophages. To date, two patients have been treated with CT-0508, an autologous adoptive cell therapy consisting of monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. For manufacturing, patients received four doses of filgrastim for monocyte mobilization prior to apheresis and adenoviral delivery of an anti-HER2 CAR. Treatment was well-tolerated, with no dose-limiting toxicities and no therapy-related toxicities of grade 4 or greater. One participant developed grade 2 CRS three days post-infusion, which resolved on the same day. Transcriptomic analysis of tumor tissue samples revealed rapid recruitment of inflammatory innate immune and naïve T cells by 8 days after infusion. By the 4-week timepoint, significant infiltration by activated and proliferating CD8+ T cells were observed. The trial is continuing to recruit patients, and the data thus far continue to indicate that CT-0508 elicits favorable changes in the tumors.