Tumour mutational burden: primary versus metastatic tissue creates systematic bias

Schnidrig, Désirée; Turajlic, Samra; Litchfield, Kevin

doi:10.1016/j.iotech.2019.11.003

Cited by 31 publications

(22 citation statements)

References 35 publications

(58 reference statements)

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“…Studies have also shown that there is a significant difference in the TMB of primary and metastatic tumors from matched patients, indicating that there could be unique neoantigens present in different tumors from the same patient. 9 , 10 It is important to target all tumors within a patient to provide an optimal clinical response. Vaccine platforms commonly use in silico prediction methods to predict neoantigens that bind with high affinity to histocompatibility leukocyte antigens (HLAs) from the patients.…”

Section: Introductionmentioning

confidence: 99%

A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation

Bhojnagarwala

Perales‐Puchalt

Cooch

et al. 2021

Molecular Therapy - Oncolytics

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Neoantigens are tumor-specific antigens that arise due to somatic mutations in the DNA of tumor cells. They represent ideal targets for cancer immunotherapy since there is minimal risk for on-target, off-tumor toxicities. Additionally, these are foreign antigens that should be immunogenic due to lack of central immune tolerance. Tumor neoantigens are predominantly passenger mutations, which do not contribute to tumorigenesis. In cases of multi-focal or metastatic tumors, different foci can have significantly different mutation profiles. This suggests that it is important to target as many neoantigens as possible to better control tumors and target multi-focal tumors within the same patient. Herein, we report a study targeting up to 40 neoantigens using a single DNA plasmid. We observed significant plasticity in the epitope strings arranged in the vaccine with regard to immune induction and tumor control. Different vaccines elicited T cell responses against multiple epitopes on the vaccine string and controlled growth of multifocal, heterogeneous tumors in a therapeutic tumor challenge. Additionally, the multi-epitope antigens induced long-term immunity and rejected a tumor re-challenge several weeks after the final vaccination. These data provide evidence that DNAencoded long antigen strings can be an important tool for immunotherapeutic vaccination against neoantigens with implications for other in vivo-delivered antigen strings.

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Section: Introductionmentioning

confidence: 99%

A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation

Bhojnagarwala

Perales‐Puchalt

Cooch

et al. 2021

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

show abstract

“…[10][11][12] Moreover, tTMB measured from metastatic tumors are higher than that from primary tumors, but this is often overlooked when comparing bTMB and tTMB. 13 Tumor mutational burden and its measurement is increasingly being incorporated into routine practice to guide therapy in cancer patients. 9 However, there is a concern that immunotherapy can be used on patients inappropriately, especially since the concordance between bTMB and .…”

Section: Introductionmentioning

confidence: 99%

Exploring real-world concordance of tissue mutation burden (TMB) from blood and tissue in patients with solid tumors

Park

et al. 2021

Preprint

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Purpose Tumor mutational burden (TMB) is an approved biomarker for immunotherapy in metastatic cancer patients. While initially measured from tissue (tTMB), TMB derived from circulating tumor DNA (ctDNA) - also known as blood TMB (bTMB) - is increasingly being used in the clinic. Currently, real-world concordance between tTMB and bTMB is not well understood. Patients and methods From October 2020 to March 2021, cancer patients who had both tTMB and bTMB results were selected. Patients were classified according to clinical variables and tumor burden, and correlation analyses or tests of independence were performed to explore any associations. Results From a total of 38 patients included in our study, 20 patients (52.6%) had non-small cell lung carcinoma and 18 (47.4%) had other cancers. Median bTMB of 9.6 mut/MB was higher than median tTMB of 4.0 mut/Mb, and the distributions of bTMB and tTMB differed significantly (n=38, p < 0.001). bTMB was positively correlated with tTMB in the total study population (Spearman ρ=0.57, p < 0.001 ) and a tTMB of 10 mut/Mb correlated with a bTMB of 21.1 mut/Mb. Dividing patients by cancer type or site of tumor biopsy resulted in significantly differing strength and degree of correlation, but dividing patients by concordant and discordant bTMB:tTMB ratio did not reveal any significantly different distributions of clinical variables or tumor burden. Conclusion bTMB was positively correlated with tTMB, and median bTMB was higher than median tTMB. Cancer type and site of tissue biopsy may influence concordance between tTMB and bTMB. Future studies with more patients may help define the optimal bTMB threshold for receiving immunotherapy, which may be different from the tTMB threshold.

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“… 10 , 11 , 12 , 13 In line with our results, TMB has been shown to vary significantly between primary and metastatic sites in the same patient, with higher rates of TMB recorded in metastases than in primary tumor. 14 A study of NSCLC specimens presented an increase of TMB in metastatic specimens with the highest in BM samples with 13 Mut/Mb compared with 6 Mut/Mb in primary lung adenocarcinoma. In addition, further differences were identified in the NSCLC metastatic sites with brain and adrenal metastases showing the highest TMB, and bone and liver metastases, the lowest TMB across all metastatic sites.…”

Section: Discussionmentioning

confidence: 98%

Tumor mutational burden and immune infiltrates in renal cell carcinoma and matched brain metastases

et al. 2021

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Background Tumor mutational burden (TMB) and density of tumor-infiltrating lymphocytes (TIL) have been postulated as predictive biomarkers for immunotherapy. Therefore, we investigated the concordance of TMB and TIL of primary/extracranial renal cell carcinoma (RCC) specimens and matched brain metastases (BM). Patients and methods Twenty specimens from 10 patients were retrieved from the Vienna Brain Metastasis Registry (6/10 primary tumor, 4/10 lung metastasis, 10/10 matched BM). TMB was assessed using the TruSight Oncology 500 gene panel with libraries sequenced on a NextSeq instrument. TIL subsets (CD3+, CD8+, CD45RO+, FOXP3+, PD-L1+) were investigated using immunohistochemistry (Ventana Benchmark Ultra system) and automated tissue analysis (Definiens software). Results No significant difference in TMB, CD3+, CD8+, CD45RO+, FOXP3+ or PD-L1+ expression was observed between extracranial and matched intracranial specimens ( P > 0.05). Higher CD8+ TIL ( P = 0.053) and CD45RO+ TIL ( P = 0.030) densities in the primary tumor compared with the intracranial samples were observed in specimens collected after exposure to systemic treatment. Neither extracranial sample origin (lung metastasis versus primary RCC) nor extracranial disease status at BM diagnosis (progressive versus stable disease) were significantly associated with TMB or TIL densities in extracranial and intracranial samples ( P > 0.05). No significant correlation was found between the median differences of TMB or TIL densities from extracranial to intracranial samples and BM-free survival. Conclusion The comparable immunological microenvironment of extra- and intracranial tumor samples in our study underscores the immunological activation also in BM from RCC, and therefore, supports the development of immune modulatory treatments also in patients with brain metastatic RCC.

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Tumour mutational burden: primary versus metastatic tissue creates systematic bias

Cited by 31 publications

References 35 publications

A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation

A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation

Exploring real-world concordance of tissue mutation burden (TMB) from blood and tissue in patients with solid tumors

Tumor mutational burden and immune infiltrates in renal cell carcinoma and matched brain metastases

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