Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer methods
Aim. Evidence-backed execution summary for Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer methods from Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.
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human
Subject model for the experiment.
- Use
- confirm full cohort details in the source paper
Detection of TP53 R175H mutation by digital droplet PCR
reagent used in the protocol.
- Use
- TP53 assays were ordered from Bio-Rad (assay identifiers dHsaCP2000105 for TP53 p.R175H c.524G>A; dHsaCP2000106 for TP53 WT). Cycling conditions were tested to ensure optimal annealing and extension temperatures and optimal separation of positive from empty droplets. Optimization was done using a known positive cont...
Extended data figures and tables
reagent used in the protocol.
- Use
- Extended Data Fig. 7 Autogene cevumeran responders evidence lower post-vaccination serum CA19-9, equivalent chemotherapy doses and comparable intratumoural T cells. ( A, B ) Fraction of biomarker-evaluable patients with detectable CA19-9 ( A ) or circulating tumour DNA (ctDNA) ( B ) in the peripheral blood at diagno...
Safety, feasibility and immunogenicity
reagent used in the protocol.
- Use
- Next, to measure the T cell responses induced by autogene cevumeran, we utilized a previously described ex vivo IFNγ ELISpot assay that detects high-magnitude T cell responses to vaccines without distinguishing CD8 + from CD4 + T cell responses. Eight out of 16 (50%) patients who received the...
T cell clonotypes and phenotypes
reagent used in the protocol.
- Use
- To confirm ELISpot assay reactivity using an orthogonal technique and to probe the diversity and specificity of autogene-cevumeran-expanded T cell clones, we developed CloneTrack. CloneTrack is a new mathematical and immunological method that uses T cell receptor (TCR) Vβ sequencing of peripheral blood sa...
Vaccine response and clinical outcome
reagent used in the protocol.
- Use
- At a median follow-up of 18 months that extended beyond the prespecified secondary end point, the median OS and RFS of the patients in the safety-evaluable cohort were not reached (Fig. ). For patients in the biomarker-evaluable cohort, the 8 autogene cevumeran responders had a median RFS that was not rea...
Vaccine clones and a micrometastasis
reagent used in the protocol.
- Use
- Patient 29 responded to autogene cevumeran with the second-highest maximal percentage of expanded blood T cells (Fig. ) that included vaccine neoantigen-specific polyfunctional CD8 + T cells (Extended Data Fig. ). Patient 29 developed increased serum CA19-9 levels with a new 7-mm liver lesion...
Methods
reagent used in the protocol.
- Use
- We conducted the study in accordance with the Declaration of Helsinki and good clinical practice guidelines. The study was approved by the institutional review board at MSK, the US Food Drug Administration and was registered on ClinicalTrials.gov ( NCT04161755 ). All participants provided written informed consent.
Immune response assays
reagent used in the protocol.
- Use
- We investigated peripheral blood samples using two independent assays. Both, per design, detect high-magnitude T cell responses to vaccines without distinguishing CD8 + from CD4 + T cell responses. IFNγ ELISpot was performed ex vivo (that is, without previous expansion in culture to capture T...
Clonality
MuTect 1.1.7 and Strelka 1.0.15 were used to call SNV and indels on pre-processed sequencing data. For the MuTect calls, dbSNP 138 and CosmicCodingMuts.vcf (v.86) were used as reference files. For the Strelka calls, we set "isSkipDepthFilters = 1" to prevent filtering-out of mutation calls fr...
- Use
- MuTect 1.1.7 and Strelka 1.0.15 were used to call SNV and indels on pre-processed sequencing data. For the MuTect calls, dbSNP 138 and CosmicCodingMuts.vcf (v.86) were used as reference files. For the Strelka calls, we set "isSkipDepthFilters = 1" to prevent filtering-out of mutation calls fr...
T cell clonotypes and phenotypes
To confirm ELISpot assay reactivity using an orthogonal technique and to probe the diversity and specificity of autogene-cevumeran-expanded T cell clones, we developed CloneTrack. CloneTrack is a new mathematical and immunological method that uses T cell receptor (TCR) Vβ sequencing of peripheral blood sa...
- Use
- To confirm ELISpot assay reactivity using an orthogonal technique and to probe the diversity and specificity of autogene-cevumeran-expanded T cell clones, we developed CloneTrack. CloneTrack is a new mathematical and immunological method that uses T cell receptor (TCR) Vβ sequencing of peripheral blood sa...
T cell clonotypes and phenotypes
We next studied the phenotype and function of autogene-cevumeran-expanded T cells. Using single-cell RNA sequencing, we found that autogene-cevumeran-expanded high-magnitude clones were CD8 + T cells that expressed lytic markers (perforin 1 and granzyme B) and cytokines (IFNγ) and resemb...
- Use
- We next studied the phenotype and function of autogene-cevumeran-expanded T cells. Using single-cell RNA sequencing, we found that autogene-cevumeran-expanded high-magnitude clones were CD8 + T cells that expressed lytic markers (perforin 1 and granzyme B) and cytokines (IFNγ) and resemb...
Vaccine clones and a micrometastasis
Patient 29 responded to autogene cevumeran with the second-highest maximal percentage of expanded blood T cells (Fig. ) that included vaccine neoantigen-specific polyfunctional CD8 + T cells (Extended Data Fig. ). Patient 29 developed increased serum CA19-9 levels with a new 7-mm liver lesion...
- Use
- Patient 29 responded to autogene cevumeran with the second-highest maximal percentage of expanded blood T cells (Fig. ) that included vaccine neoantigen-specific polyfunctional CD8 + T cells (Extended Data Fig. ). Patient 29 developed increased serum CA19-9 levels with a new 7-mm liver lesion...
Immune response assays
To confirm IFNγ ELISpot results using an orthogonal technique, we used TCR Vβ sequencing-based CloneTrack to detect greater than twofold in vivo expansion of T cell clones to vaccines in a non-antigen-specific manner. Clones that expanded at different treatment times (before and after atezolizumab; b...
- Use
- To confirm IFNγ ELISpot results using an orthogonal technique, we used TCR Vβ sequencing-based CloneTrack to detect greater than twofold in vivo expansion of T cell clones to vaccines in a non-antigen-specific manner. Clones that expanded at different treatment times (before and after atezolizumab; b...
Mutation identification and neoantigen selection
DNA was extracted from PBMCs. DNA and RNA were extracted from tumours. Expressed non-synonymous mutations and HLA type were identified by whole-exome sequencing of patient-specific tumour-normal pairs and tumour RNA sequencing. Neoantigens were bioinformatically predicted and ranked by immunogenicity as previo...
- Use
- DNA was extracted from PBMCs. DNA and RNA were extracted from tumours. Expressed non-synonymous mutations and HLA type were identified by whole-exome sequencing of patient-specific tumour-normal pairs and tumour RNA sequencing. Neoantigens were bioinformatically predicted and ranked by immunogenicity as previo...
Somatic and germline mutation testing
For the detection of somatic tumour mutations in key cancer genes, we used MSK-IMPACT, a previously published targeted tumour-sequencing test that covers 468 cancer genes.
- Use
- For the detection of somatic tumour mutations in key cancer genes, we used MSK-IMPACT, a previously published targeted tumour-sequencing test that covers 468 cancer genes.
Somatic and germline mutation testing
For the detection of germline mutations, we utilized the MSK-IMPACT panel to detect pathogenic germline variants. In brief, gDNA was enriched for targeted regions using a hybridization-based protocol and sequenced on an Illumina HiSeq instrument. Sequence reads were aligned to the GRCh37/hg19 reference human genome...
- Use
- For the detection of germline mutations, we utilized the MSK-IMPACT panel to detect pathogenic germline variants. In brief, gDNA was enriched for targeted regions using a hybridization-based protocol and sequenced on an Illumina HiSeq instrument. Sequence reads were aligned to the GRCh37/hg19 reference human genome...
Immune response
Software used for acquisition, scoring, statistics, or reporting.
- Use
- Multiscreen filter plates (Merck Millipore), precoated with antibodies specific for IFNγ (Mabtech), were washed with PBS and blocked with X-VIVO 15 (Lonza) containing 2% human serum albumin (CSL-Behring) for 1-5 h. Next, 3 × 10 5 effector cells per well were stimulated for 16-...
Statistical analyses
Software used for acquisition, scoring, statistics, or reporting.
- Use
- Safety end points are presented descriptively as percentages. Sample sizes ( n ) represent the number of patients, tumours, T cell clones or neoantigens. We analysed feasibility as the statistical equivalence between benchmarked and achieved treatment times. Here, we defined a delay of <1 week as the zon...
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Patients
After surgery, we included patients with pathologically confirmed PDAC with R0/R1 margins. Additional eligibility criteria and ethical study conduct information are in the protocol (Supplementary Data ). We aimed to accrue 20 evaluable patients.
Surgery
Patients underwent open pancreaticoduodenectomy or either open or laparoscopic distal pancreatectomy and splenectomy at MSK. We then transported tumour blocks with the most (minimum ≥10%) histological tumour content with matched blood to BioNTech.
Main
PDAC is the third leading cause of cancer death in the United States and the seventh worldwide. With an increasing incidence, and a survival rate of 12% that has remained largely stagnant for nearly 60 years, PDAC is projected to cause even greater global cancer deaths by 2025 (refs., ). Surgery is the only curative treatment for PDAC. Yet, despite surgery, nearly 90% of patients have disease recurrence at a median of 7-9 months,, and the 5-year overall survival (OS) is only 8-10%,. Although adjuvant multiagent chemotherapies delay recurrence and are standard of care in surgically resected PDAC, nearly 80% of patients have disease recurrence at around 14 months, and their 5-year OS is <30%. Radiation, biologics and targeted therapies are also ineffective.
Main
To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individualized mRNA neoantigen vaccine containing up to 20 major histocompatibility complex class I (MHCI) and MHC class II (MHCII) restricted neoantigens in lipoplex nanoparticles intravenously delivered; Individualized NeoAntigen-Specific Therapy (iNeST), BioNTech and Genentech) and mFOLFIRINOX in patients with surgically resectable PDAC (Fig. ) to: (1) amplify neoantigen-specific T cells inhibited by PD-1 signalling; and (2) prime naive T cells to vaccine neoantigens. Fig. 1 Individualized mRNA neoantigen vaccines are safe, feasible and immunogenic in patients with PDAC. a, b, Trial design ( a ) and consolidated standards of reporting trials diagram ( b ). c, Percentage of grade...
Safety, feasibility and immunogenicity
From December 2019 to August 2021, we enrolled 34 patients, of which 28 patients (Fig. ) underwent surgery. We then treated 19 patients with atezolizumab, of which 16 patients received subsequent autogene cevumeran. Fifteen out of these 16 patients also received subsequent mFOLFIRINOX (Fig. ). We analysed safety in a safety-evaluable cohort ( n = 19 patients treated with atezolizumab, n = 16 treated with autogene cevumeran), and we correlated immune response to RFS in a biomarker-evaluable cohort ( n = 16 patients treated with atezolizumab and autogene cevumeran). All 19 evaluable participants had clinical characteristics typical of patients with resectable PDAC (Extended Data Fig. ). All patients were treated and followed at the Memorial Sloan Kettering Cancer Center (MSK) during and beyond the enrolment period.
Safety, feasibility and immunogenicity
None of the 19 patients treated with atezolizumab in the safety-evaluable cohort had grade 3 or higher adverse events (AEs; Fig. ). One out of 16 (6%) patients treated with autogene cevumeran in the safety-evaluable cohort had grade 3 AEs (fever and hypertension; Fig. ). All 16 patients (100%) who received autogene cevumeran had grade 1-2 AEs (Extended Data Fig. ). We administered atezolizumab and autogene cevumeran at median times within 1 and 3 days of respective benchmarked times (median time to atezolizumab was 6.1 weeks (range of 4.3-7.9 weeks); median time to autogene cevumeran was 9.4 weeks (range of 7.4-11.0 weeks); Fig. ). Only 1 patient out of 19 (5%) had insufficient neoantigens that led to non-manufacture of the vaccine (Fig. ). Three out of 16 patients (19%) did not receive all 9 vaccine doses (Fig. ),...
Safety, feasibility and immunogenicity
Next, to measure the T cell responses induced by autogene cevumeran, we utilized a previously described ex vivo IFNγ ELISpot assay that detects high-magnitude T cell responses to vaccines without distinguishing CD8 + from CD4 + T cell responses. Eight out of 16 (50%) patients who received the vaccine generated T cell responses that were detected by ex vivo IFNγ ELISpot, and were deemed autogene cevumeran responders (Fig. ). By testing each specific target included in the neoantigen vaccines, we detected that 25 out of the 230 neoantigens (11%) administered across all patients who were evaluable at the single-target level induced a T cell response of sufficient high magnitude to be detectable by ex vivo IFNγ ELISpot (Fig. and Extended Data Fig. ). Half of all the patients who received the vaccine mounted neoantigen-specific T cell...
T cell clonotypes and phenotypes
We next studied the phenotype and function of autogene-cevumeran-expanded T cells. Using single-cell RNA sequencing, we found that autogene-cevumeran-expanded high-magnitude clones were CD8 + T cells that expressed lytic markers (perforin 1 and granzyme B) and cytokines (IFNγ) and resembled effector T cells induced by protective viral vaccines (Fig. and Extended Data Fig. ). Consistently, peripheral blood samples collected after vaccination contained polyfunctional CD8 + T cells but not CD4 + T cells that produced cytokines (IFNγ and TNF) and degranulated on in vitro rechallenge with both long neopeptides (Fig. and Extended Data Fig. ) and MHCI-restricted minimal epitopes (Fig. and Extended Data Fig. ). Notably, autogene-cevumeran-expanded T cells maintained functionality despite post-vaccination mFOLFIRINOX treatment...
Measurement outputs
What raw and processed outputs should exist?
TP53 assays were ordered from Bio-Rad (assay identifiers dHsaCP2000105 for TP53 p.R175H c.524G>A; dHsaCP2000106 for TP53 WT). Cycling conditions were tested to ensure optimal an...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individua...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
At a median follow-up of 18 months that extended beyond the prespecified secondary end point, the median OS and RFS of the patients in the safety-evaluable cohort were not...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
As autogene cevumeran induced high-magnitude T cell responses specific to 25 out of 106 vaccine-encoded neoantigens (24%) in responders (Extended Data Fig. ), we searched...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Analysis plan
How should the outputs become interpretable results?
Acquisition
Collect raw experimental outputs with enough metadata to preserve sample identity, condition, and timing.
inferred from protocolPreprocessing / cleaning
Extended Data Fig.
from paperScoring or quantification
Quantify the primary readouts for this experiment: TP53 assays were ordered from Bio-Rad (assay identifiers dHsaCP2000105 for TP53 p.R175H c.524G>A; dHsaCP2000106 for TP53 WT). Cycling conditions were tested to ensure optimal an...; To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individua...; At a median follow-up of 18 months that extended beyond the prespecified secondary end point, the median OS and RFS of the patients in the safety-evaluable cohort were not...; As autogene cevumeran induced high-magnitude T cell responses specific to 25 out of 106 vaccine-encoded neoantigens (24%) in responders (Extended Data Fig. ), we searched....
from paperStatistical comparison
Extended Data Fig. 7 Autogene cevumeran responders evidence lower post-vaccination serum CA19-9, equivalent chemotherapy doses and comparable intratumoural T cells. ( A, B ) Fra...; To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individua...; To confirm ELISpot assay reactivity using an orthogonal technique and to probe the diversity and specificity of autogene-cevumeran-expanded T cell clones, we developed CloneTrac...; Multiscreen filter plates (Merck Millipore), precoated with antibodies specific for IFNγ (Mabtech), were washed with PBS and blocked with X-VIVO 15 (Lonza) containing 2% hu...
from paperReporting output
Report representative outputs alongside summary comparisons for TP53 assays were ordered from Bio-Rad (assay identifiers dHsaCP2000105 for TP53 p.R175H c.524G>A; dHsaCP2000106 for TP53 WT). Cycling conditions were tested to ensure optimal an..., To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individua..., At a median follow-up of 18 months that extended beyond the prespecified secondary end point, the median OS and RFS of the patients in the safety-evaluable cohort were not..., As autogene cevumeran induced high-magnitude T cell responses specific to 25 out of 106 vaccine-encoded neoantigens (24%) in responders (Extended Data Fig. ), we searched....
inferred from protocolStructured statistical methods
Extended Data Fig. 7 Autogene cevumeran responders evidence lower post-vaccination serum CA19-9, equivalent chemotherapy doses and comparable intratumoural T cells. ( A, B ) Fra...; To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individua...; To confirm ELISpot assay reactivity using an orthogonal technique and to probe the diversity and specificity of autogene-cevumeran-expanded T cell clones, we developed CloneTrac...; Multiscreen filter plates (Merck Millipore), precoated with antibodies specific for IFNγ (Mabtech), were washed with PBS and blocked with X-VIVO 15 (Lonza) containing 2% hu...
source structuredSource and audit
What supports the facts on this page?
Evidence quotes (8)
After surgery, we included patients with pathologically confirmed PDAC with R0/R1 margins. Additional eligibility criteria and ethical study conduct information are in the protocol (Supplementary Data ). We aimed to accrue 20 evaluable patients.
Patients underwent open pancreaticoduodenectomy or either open or laparoscopic distal pancreatectomy and splenectomy at MSK. We then transported tumour blocks with the most (minimum ≥10%) histological tumour content with matched blood to BioNTech.
PDAC is the third leading cause of cancer death in the United States and the seventh worldwide. With an increasing incidence, and a survival rate of 12% that has remained largely stagnant for nearly 60 years, PDAC is projected to cause even greater global cancer deaths by 2025 (refs., ). Surgery is the only curative treatment for PDAC. Yet, despite surgery, nearly 90% of patients have disease recurrence at a median of 7-9 months,, and the 5-year overall survival (OS) is only 8-10%,. Although adjuvant multiagent chemotherapies delay recurrence and are standard of care in surgically resected PDAC, nearly 80% of patients have disease recurrence at around 14 months, and their 5-year OS is <30%. Radiation, biologics and targeted therapies are also ineffective.
To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individualized mRNA neoantigen vaccine containing up to 20 major histocompatibility complex class I (MHCI) and MHC class II (MHCII) restricted neoantigens in lipoplex nanoparticles intravenously delivered; Individualized NeoAntigen-Specific Therapy (iNeST), BioNTech and Genentech) and mFOLFIRINOX in patients with surgically resectable PDAC (Fig. ) to: (1) amplify neoantigen-specific T cells inhibited by PD-1 signalling; and (2) prime naive T cells to vaccine neoantigens. Fig. 1 Individualized mRNA neoantigen vaccines are safe, feasible and immunogenic in patients with PDAC. a, b, Trial design ( a ) and consolidated standards of reporting trials diagram ( b ). c, Percentage of grade 3 AEs attributable to atezolizumab and autogene cevumeran (vaccine) in atezolizumab ( n = 19) and vaccine ( n = 16) safety-evaluable patients. Blue line indicates the study-defined safety threshold (25%). d, Achieved and benchmarked times to atezolizumab (left) and first vaccine dose (middle)...
From December 2019 to August 2021, we enrolled 34 patients, of which 28 patients (Fig. ) underwent surgery. We then treated 19 patients with atezolizumab, of which 16 patients received subsequent autogene cevumeran. Fifteen out of these 16 patients also received subsequent mFOLFIRINOX (Fig. ). We analysed safety in a safety-evaluable cohort ( n = 19 patients treated with atezolizumab, n = 16 treated with autogene cevumeran), and we correlated immune response to RFS in a biomarker-evaluable cohort ( n = 16 patients treated with atezolizumab and autogene cevumeran). All 19 evaluable participants had clinical characteristics typical of patients with resectable PDAC (Extended Data Fig. ). All patients were treated and followed at the Memorial Sloan Kettering Cancer Center (MSK) during and beyond the enrolment period.
None of the 19 patients treated with atezolizumab in the safety-evaluable cohort had grade 3 or higher adverse events (AEs; Fig. ). One out of 16 (6%) patients treated with autogene cevumeran in the safety-evaluable cohort had grade 3 AEs (fever and hypertension; Fig. ). All 16 patients (100%) who received autogene cevumeran had grade 1-2 AEs (Extended Data Fig. ). We administered atezolizumab and autogene cevumeran at median times within 1 and 3 days of respective benchmarked times (median time to atezolizumab was 6.1 weeks (range of 4.3-7.9 weeks); median time to autogene cevumeran was 9.4 weeks (range of 7.4-11.0 weeks); Fig. ). Only 1 patient out of 19 (5%) had insufficient neoantigens that led to non-manufacture of the vaccine (Fig. ). Three out of 16 patients (19%) did not receive all 9 vaccine doses (Fig. ), which was due to progression, death or mFOLFIRINOX toxicity. Thus, autogene cevumeran can be rapidly administered even after complex oncologic surgery.
Next, to measure the T cell responses induced by autogene cevumeran, we utilized a previously described ex vivo IFNγ ELISpot assay that detects high-magnitude T cell responses to vaccines without distinguishing CD8 + from CD4 + T cell responses. Eight out of 16 (50%) patients who received the vaccine generated T cell responses that were detected by ex vivo IFNγ ELISpot, and were deemed autogene cevumeran responders (Fig. ). By testing each specific target included in the neoantigen vaccines, we detected that 25 out of the 230 neoantigens (11%) administered across all patients who were evaluable at the single-target level induced a T cell response of sufficient high magnitude to be detectable by ex vivo IFNγ ELISpot (Fig. and Extended Data Fig. ). Half of all the patients who received the vaccine mounted neoantigen-specific T cell responses against at least one vaccine neoantigen (median = 2, range = 1-8; Extended Data Fig. ). Furthermore, half of these responses were polytopic, targeting more than one vaccine neoantigen (Fig. ). No T cell responses against vaccine neoantigens were detecta...
We next studied the phenotype and function of autogene-cevumeran-expanded T cells. Using single-cell RNA sequencing, we found that autogene-cevumeran-expanded high-magnitude clones were CD8 + T cells that expressed lytic markers (perforin 1 and granzyme B) and cytokines (IFNγ) and resembled effector T cells induced by protective viral vaccines (Fig. and Extended Data Fig. ). Consistently, peripheral blood samples collected after vaccination contained polyfunctional CD8 + T cells but not CD4 + T cells that produced cytokines (IFNγ and TNF) and degranulated on in vitro rechallenge with both long neopeptides (Fig. and Extended Data Fig. ) and MHCI-restricted minimal epitopes (Fig. and Extended Data Fig. ). Notably, autogene-cevumeran-expanded T cells maintained functionality despite post-vaccination mFOLFIRINOX treatment, with persistent IFNγ production (Fig. ), uniform re-expansion with a vaccine booster in all responders (Fig. ) and sustained persistence as high as 2.5% of all blood T cells up to 2 years after surgery (Fig. and Supplementary Table ). Furthermore, vaccine boosters re-expanded iden...
Machine-readable layer
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"name": "Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer methods",
"description": "Evidence-backed execution summary for Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer methods from Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.",
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{
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"text": "After surgery, we included patients with pathologically confirmed PDAC with R0/R1 margins. Additional eligibility criteria and ethical study conduct information are in the protocol (Supplementary Data ). We aimed to accrue 20 evaluable patients."
},
{
"@type": "HowToStep",
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"text": "Patients underwent open pancreaticoduodenectomy or either open or laparoscopic distal pancreatectomy and splenectomy at MSK. We then transported tumour blocks with the most (minimum ≥10%) histological tumour content with matched blood to BioNTech."
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"text": "PDAC is the third leading cause of cancer death in the United States and the seventh worldwide. With an increasing incidence, and a survival rate of 12% that has remained largely stagnant for nearly 60 years, PDAC is projected to cause even greater global cancer deaths by 2025 (refs., ). Surgery is the only curative treatment for PDAC. Yet, despite surgery, nearly 90% of patients have disease recurrence at a median of 7-9 months,, and the 5-year overall survival (OS) is only 8-10%,. Although adjuvant multiagent chemotherapies delay recurrence and are standard of care in surgically resected PDAC, nearly 80% of patients have disease recurrence at around 14 months, and their 5-year OS is <30%. Radiation, biologics and targeted therapies are also ineffective."
},
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"@type": "HowToStep",
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"name": "Main",
"text": "To test this hypothesis, we conducted an investigator-initiated, phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran, (an individualized mRNA neoantigen vaccine containing up to 20 major histocompatibility complex class I (MHCI) and MHC class II (MHCII) restricted neoantigens in lipoplex nanoparticles intravenously delivered; Individualized NeoAntigen-Specific Therapy (iNeST), BioNTech and Genentech) and mFOLFIRINOX in patients with surgically resectable PDAC (Fig. ) to: (1) amplify neoantigen-specific T cells inhibited by PD-1 signalling; and (2) prime naive T cells to vaccine neoantigens. Fig. 1 Individualized mRNA neoantigen vaccines are safe, feasible and immunogenic in patients with PDAC. a, b, Trial design ( a ) and consolidated standards of reporting trials diagram ( b ). c, Percentage of grade..."
},
{
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"text": "From December 2019 to August 2021, we enrolled 34 patients, of which 28 patients (Fig. ) underwent surgery. We then treated 19 patients with atezolizumab, of which 16 patients received subsequent autogene cevumeran. Fifteen out of these 16 patients also received subsequent mFOLFIRINOX (Fig. ). We analysed safety in a safety-evaluable cohort ( n = 19 patients treated with atezolizumab, n = 16 treated with autogene cevumeran), and we correlated immune response to RFS in a biomarker-evaluable cohort ( n = 16 patients treated with atezolizumab and autogene cevumeran). All 19 evaluable participants had clinical characteristics typical of patients with resectable PDAC (Extended Data Fig. ). All patients were treated and followed at the Memorial Sloan Kettering Cancer Center (MSK) during and beyond the enrolment period."
},
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"@type": "HowToStep",
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"name": "Safety, feasibility and immunogenicity",
"text": "None of the 19 patients treated with atezolizumab in the safety-evaluable cohort had grade 3 or higher adverse events (AEs; Fig. ). One out of 16 (6%) patients treated with autogene cevumeran in the safety-evaluable cohort had grade 3 AEs (fever and hypertension; Fig. ). All 16 patients (100%) who received autogene cevumeran had grade 1-2 AEs (Extended Data Fig. ). We administered atezolizumab and autogene cevumeran at median times within 1 and 3 days of respective benchmarked times (median time to atezolizumab was 6.1 weeks (range of 4.3-7.9 weeks); median time to autogene cevumeran was 9.4 weeks (range of 7.4-11.0 weeks); Fig. ). Only 1 patient out of 19 (5%) had insufficient neoantigens that led to non-manufacture of the vaccine (Fig. ). Three out of 16 patients (19%) did not receive all 9 vaccine doses (Fig. ),..."
},
{
"@type": "HowToStep",
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"name": "Safety, feasibility and immunogenicity",
"text": "Next, to measure the T cell responses induced by autogene cevumeran, we utilized a previously described ex vivo IFNγ ELISpot assay that detects high-magnitude T cell responses to vaccines without distinguishing CD8 + from CD4 + T cell responses. Eight out of 16 (50%) patients who received the vaccine generated T cell responses that were detected by ex vivo IFNγ ELISpot, and were deemed autogene cevumeran responders (Fig. ). By testing each specific target included in the neoantigen vaccines, we detected that 25 out of the 230 neoantigens (11%) administered across all patients who were evaluable at the single-target level induced a T cell response of sufficient high magnitude to be detectable by ex vivo IFNγ ELISpot (Fig. and Extended Data Fig. ). Half of all the patients who received the vaccine mounted neoantigen-specific T cell..."
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