Association of High Tumor Mutation Burden in Non–Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels

Ricciuti, Biagio; Wang, Xinan; Alessi, Joao; Rizvi, Hira; Mahadevan, Navin R.; Li, Yvonne Y.; Polio, Andrew; Lindsay, James; Umeton, Renato; Sinha, Rileen; Vokes, Natalie I.; Recondo, Gonzálo; Lamberti, Giuseppe; Lawrence, Marissa; Vaz, Victor R.; Leonardi, Giulia C.; Plodkowski, Andrew J.; Gupta, Hersh; Cherniack, Andrew D.; Tolstorukov, Michael Y.; Sharma, Bijaya; Felt, Kristen D.; Gainor, Justin F.; Ravi, Arvind; Getz, Gad; Schalper, Kurt A.; Henick, Brian S.; Forde, Patrick M.; Anagnostou, Valsamo; Jänne, Pasi A.; Allen, Eliezer M. Van; Nishino, Mizuki; Sholl, Lynette M.; Christiani, David C.; Lin, Xihong; Rodig, Scott J.; Hellmann, Matthew D.; Awad, Mark M.

doi:10.1001/jamaoncol.2022.1981

Cited by 135 publications

(86 citation statements)

References 30 publications

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“…Fourth, the issue raised by nucleoside modification and codon optimization of mRNA needs to be addressed to ensure efficient and accurate translation of full‐length polypeptides that are properly folded 49,298–300 . Fifth, mRNA cancer vaccines in combination with other immunotherapies should be investigated to determine which combinations exert synergetic effects in cancer treatment 66,241,301,302 . Lastly, it is important to determine whether mRNA vaccines are processed and function in the same way in animal models and in humans, because some mRNA vaccines, which showed immunogenicity in preclinical animal trials, have generated disappointing results in human trials 28,91,175,303 …”

Section: Discussionmentioning

confidence: 99%

“…More DNA mutations can produce more candidate peptides and lead to an increase in tumor antigens that can be presented. Several studies have demonstrated that tumor patients with a high tumor mutational burden are often associated with stronger T cell response and better clinical outcomes 241,242 . Therefore, multitargeting mRNA vaccines have shown promising prospects in the treatment of highly immunogenic melanomas but have not progressed as well in other tumor types 243–245 .…”

Section: Mrna Cancer Vaccinesmentioning

confidence: 99%

“…Several studies have demonstrated that tumor patients with a high tumor mutational burden are often associated with stronger T cell response and better clinical outcomes. 241,242 Therefore, multitargeting mRNA vaccines have shown promising prospects in the treatment of highly immunogenic melanomas but have not progressed as well in other tumor types. [243][244][245] For example, the mRNA vaccine BI-1361849 (formerly called CV9202), developed by Curevac, is currently undergoing phase I/II clinical trials for treatment of NSCLC.…”

Section: Mrna Vaccines Simultaneously Encoding Multiple Taasmentioning

confidence: 99%

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mRNA vaccines in the prevention and treatment of diseases

Duan

Yang

et al. 2022

MedComm

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Messenger ribonucleic acid (mRNA) vaccines made their successful public debut in the effort against the COVID‐19 outbreak starting in late 2019, although the history of mRNA vaccines can be traced back decades. This review provides an overview to discuss the historical course and present situation of mRNA vaccine development in addition to some basic concepts that underly mRNA vaccines. We discuss the general preparation and manufacturing of mRNA vaccines and also discuss the scientific advances in the in vivo delivery system and evaluate popular approaches (i.e., lipid nanoparticle and protamine) in detail. Next, we highlight the clinical value of mRNA vaccines as potent candidates for therapeutic treatment and discuss clinical progress in the treatment of cancer and coronavirus disease 2019. Data suggest that mRNA vaccines, with several prominent advantages, have achieved encouraging results and increasing attention due to tremendous potential in disease management. Finally, we suggest some potential directions worthy of further investigation and optimization. In addition to basic research, studies that help to facilitate storage and transportation will be indispensable for practical applications.

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Section: Discussionmentioning

confidence: 99%

Section: Mrna Cancer Vaccinesmentioning

confidence: 99%

Section: Mrna Vaccines Simultaneously Encoding Multiple Taasmentioning

confidence: 99%

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mRNA vaccines in the prevention and treatment of diseases

Duan

Yang

et al. 2022

MedComm

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“…Additionally, TMB status is an important predictive biomarker with high TMB predicting improved objective response to durable benefit, and progression-free survival independent of PD-L1 expression [ 72 ]. High TMB in NSCLC is associated with immune cell infiltration and an inflammatory T-cell mediated response which may explain the increased sensitivity to immunotherapy [ 73 ].…”

Section: Potential Clinical Utility Of Emerging Subtypesmentioning

confidence: 99%

Emerging Biomarkers and the Changing Landscape of Small Cell Lung Cancer

Keogh

Finn

Radonic

2022

Cancers

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Small cell lung cancer (SCLC) is a high-grade neuroendocrine malignancy with an aggressive behavior and dismal prognosis. 5-year overall survival remains a disappointing 7%. Genomically, SCLCs are homogeneous compared to non-small cell lung cancers and are characterized almost always by functional inactivation of RB1 and TP53 with no actionable mutations. Additionally, SCLCs histologically appear uniform. Thus, SCLCs are currently managed as a single disease with platinum-based chemotherapy remaining the cornerstone of treatment. Recent studies have identified expression of dominant transcriptional signatures which may permit classification of SCLCs into four biologically distinct subtypes, namely, SCLC-A, SCLC-N, SCLC-P, and SCLC-I. These groups are readily detectable by immunohistochemistry and also have potential predictive utility for emerging therapies, including PARPi, immune checkpoint inhibitors, and DLL3 targeted therapies. In contrast with their histology, studies have identified that SCLCs display both inter- and intra-tumoral heterogeneity. Identification of subpopulations of cells with high expression of PLCG2 has been linked with risk of metastasis. SCLCs also display subtype switching under therapy pressure which may contribute furthermore to metastatic ability and chemoresistance. In this review, we summarize the recent developments in the understanding of the biology of SCLCs, and discuss the potential diagnostic, prognostic, and treatment opportunities the four proposed subtypes may present for the future. We also discuss the emerging evidence of tumor heterogeneity and plasticity in SCLCs which have been implicated in metastasis and acquired therapeutic resistance seen in these aggressive tumors.

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“…Therefore, discoveries from these basic studies can help to develop future therapeutics or new diagnostics, prognostics, or predictive biomarkers [ 5 , 8 , 11 , 12 ]. In particular, tissue and circulating biomarkers from the coding and non-coding regions of the genome that are predictive of the response or resistance to different immunotherapies or targeted therapies are currently being evaluated or used in clinical trials or, more recently, in daily practice [ 1 , 2 , 10 , 13 , 14 , 15 , 16 , 17 ]. Certain biomarkers are also being tested but may be envisaged as optimizing approaches to precision medicine for NSCLC patients [ 5 , 7 , 18 ].…”

mentioning

confidence: 99%