Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies

Kerepesi, Csaba; Bakács, Tibor; Moss, Ralph W.; Slavin, Shimon; Anderson, Colin C.

doi:10.1007/s00262-020-02543-6

Cited by 21 publications

(14 citation statements)

References 20 publications

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“…Whole exome sequencing of the mutagenized YUMM1.7-CM clone revealed that nearly 15% of the acquired base substitutions, cause amino acid changes that are likely to contribute to neoantigen formation and improved engagement of immune system. The notion that neoantigen formation enhances antitumor immunogenicity and improves responses to ICB therapy is supported by clinical outcomes demonstrating that tumors with high mutational loads are more likely to respond to ICB therapies (2,37), rendering the mutational burden an important, albeit imperfect predictor of response to ICB (3,4,38,39). Examples from the clinic include subpopulations of colon cancer patients with DNA mismatch repair deficiency characterized by high tumoral mutation burden and elevated neoantigens, which have shown high response rates to anti-PD-1 checkpoint blockade (7,40,41).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

Gorgun¹,

Widen²,

Tyler³

et al. 2021

Front. Oncol.

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Sequencing data from different types of cancers including melanomas demonstrate that tumors with high mutational loads are more likely to respond to immune checkpoint blockade (ICB) therapies. We have previously shown that low-dose intratumoral injection of the chemotherapeutic DNA damaging drug cisplatin activates intrinsic mutagenic DNA damage tolerance pathway, and when combined with ICB regimen leads to tumor regression in the mouse YUMM1.7 melanoma model. We now report that tumors generated with an in vitro cisplatin-mutagenized YUMM1.7 clone (YUMM1.7-CM) regress in response to ICB, while an identical ICB regimen alone fails to suppress growth of tumors generated with the parental YUMM1.7 cells. Regressing YUMM1.7-CM tumors show greater infiltration of CD8 T lymphocytes, higher granzyme B expression, and higher tumoral cell death. Similarly, ex-vivo, immune cells isolated from YUMM1.7-CM tumors-draining lymph nodes (TDLNs) co-incubated with cultured YUMM1.7-CM cells, eliminate the tumor cells more efficiently than immune cells isolated from TDLNs of YUMM1.7 tumor-bearing mice. Collectively, our findings show that in vitro induced cisplatin mutations potentiate the antitumor immune response and ICB efficacy, akin to tumor regression achieved in the parental YUMM1.7 model by ICB administered in conjunction with intratumoral cisplatin injection. Hence, our data uphold the role of tumoral mutation burden in improving immune surveillance and response to ICB, suggesting a path for expanding the range of patients benefiting from ICB therapy.

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Section: Discussionmentioning

confidence: 99%

Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

Gorgun¹,

Widen²,

Tyler³

et al. 2021

Front. Oncol.

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“…Although a limited transformation is too weak in itself to instigate a tumor eradicating T-cell attack, with immune checkpoint blockade T cells are more effective against “altered self” resulting in better OS [ 45 ]. Not unexpectedly, a significant positive correlation was found between the reporting odds ratio (ROR) of reporting an irAE during anti-CTLA-4, anti-PD-1, and anti-CTLA-4/anti-PD-1 immune combination therapies and the corresponding TMB in 7677 patients across 19 cancer types [ 46 ]. Consistent with this, Berner et al demonstrated in NSCLC that T cells recognize and target shared tumor and skin antigens during ICI therapy resulting in autoimmune-mediated skin toxicity and tumor regression [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers – a retrospective study of a single institution

Kleef¹,

Nagy²,

Baierl

et al. 2020

Cancer Immunol Immunother

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The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0–92.8%), at 9 months was 73.5% (95% CI, 66.2–81.7%), at 12 months was 66.5% (95% CI, 58.6–75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy.

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“…Studies have revealed that TMB in dMMR/MSI-H CRCs is significantly higher than that in pMMR/MSI-L CRCs ( 48 , 67 – 69 ), and an increased amount of TMB in dMMR/MSI-H tumours can result in a 20-time higher rate of mutation and a stronger immune response than pMMR/MSI-L tumours ( 52 , 53 , 58 ), which are reflected in the very different composition and function of immune infiltrates in the TIME ( 70 – 73 ). Therefore, TMB appears to be an important biomarker for patients with dMMR/MSI-H CRC in response to anti-PD-1 therapy ( 68 , 74 – 77 ).…”

Section: The Possible Mechanisms Leading To a Distinct Therapeutic Efmentioning

confidence: 99%

The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses

Cui

2021

Front. Oncol.

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Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more “sensitive” in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.

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Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies

Cited by 21 publications

References 20 publications

Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

Enhanced Antitumor Response to Immune Checkpoint Blockade Exerted by Cisplatin-Induced Mutagenesis in a Murine Melanoma Model

Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers – a retrospective study of a single institution

The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses

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