Metastatic Melanoma Patient Had a Complete Response with Clonal Expansion after Whole Brain Radiation and PD-1 Blockade

Haymaker, Cara; Kim, Dae Won; Uemura, Marc; Vence, Luis M.; Phillip, Ann; McQuail, Natalie; Brown, Paul D.; Fernandez, Irina; Hudgens, Courtney W.; Creasy, Caitlin; Hwu, Wen Jen; Sharma, Padmanee; Tetzlaff, Michael T.; Allison, James P.; Hwu, Patrick; Bernatchez, Chantale; Diab, Adi

doi:10.1158/2326-6066.cir-16-0223

Cited by 44 publications

(33 citation statements)

References 24 publications

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“…The same T cell clone was found in peripheral blood at the frequency of 6.1% before the treatment and was expanded to 21.0% at week 10. This frequency is similar to that reported in a melanoma patient who showed complete radiological response [20], thus monitoring T cell clonal dynamics using this comprehensive approach (i.e. analyses of entire repertoire) may reflect response to therapy more accurately.…”

Section: Discussionsupporting

confidence: 83%

“…The assessment of these processes at clonal levels of T cells has recently been achieved by advances in high-throughput sequencing technologies [16,17], which have enabled us to identify millions of individual TCR sequences and provide the opportunity to track each of them longitudinally. Previous analyses of samples at two time-points (before and after the treatment) in a small cohort of patients revealed correlation between clonal expansion of certain T cells and clinical responses to immune checkpoint blockades [18][19][20]. Such findings are consistent with other reports which suggested of the patient.…”

Section: Introductionsupporting

confidence: 88%

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Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

Olugbile¹,

Park²,

Szeto³

et al. 2017

J Cancer Sci Ther

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Purpose: Antibodies that target immune checkpoint molecules have demonstrated significant and durable clinical benefit through re-activation and proliferation of pre-existing tumor-infiltrating CD8 + T cells in a broad range of tumor types including lung cancer. Detailed characterization of T cell dynamics at clonal levels using nextgeneration T cell receptor (TCR) sequencing in large cohorts of lung cancer patients is yet reported. Methods:We performed TCR sequencing of peripheral blood samples (and some tumors) obtained from 27 lung cancer patients undergoing single/combined immune checkpoint blockade therapies. Results:In one responder, we found expansion of a single T cell clone (approximately 20% of the all TCR reads) in a metastatic subcutaneous lesion that showed pathologic complete response on day 17 of treatment. The same TCR CDR3 sequence was detected in 6.1% of TCR reads in the peripheral blood prior to treatment initiation and the expansion remained persistent in peripheral blood at 21.0% at week 10 and 24.3% at week 48. In other patients who showed durable response, we also found persistent oligoclonal T cell expansion in their peripheral blood which was not observed in non-responders even while they remained on therapy. Conclusion:We found sustained expansion of oligoclonal T cell clones in lung cancer patients who had durable response to immune checkpoint blockade. This suggests possible use of longitudinal TCR sequencing to assist clinical decision-making, assess synergism with other agents, and most importantly facilitate rational development of alternative treatment strategies for non-responders.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionsupporting

confidence: 88%

Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

Olugbile¹,

Park²,

Szeto³

et al. 2017

J Cancer Sci Ther

View full text Add to dashboard Cite

show abstract

“…Furthermore, we showed that the T‐cell receptor (TCR) repertoire of tumor‐infiltrated T cells might be useful information for the evaluation or assessment of the immune microenvironment . Recent reports, including ours, suggested that durable response to immune checkpoint blockade correlated with early and sustained expansion of a few dominant T‐cell clones in peripheral blood, and that TCR sequencing can be used to detect early signs of response/resistance to immune checkpoint blockade …”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 81%

“…8 Recent reports, including ours, suggested that durable response to immune checkpoint blockade correlated with early and sustained expansion of a few dominant T-cell clones in peripheral blood, and that TCR sequencing can be used to detect early signs of response/resistance to immune checkpoint blockade. 11,12 A series of studies have also addressed the relationship between mutational burden and immunotherapeutic outcome. Early studies supported the hypothesis that the extent of DNA damage is correlated with therapeutic response in melanoma patients treated with anti-CTLA-4 antibody, 13 and non-small-cell lung cancer patients treated with anti-PD1 antibody.…”

Section: Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

2018

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Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, from which the majority of patients experienced no or minimum clinical benefit. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer‐specific immune targets. Highly tumor‐specific antigens, neoantigens, are generated by somatic mutations that are not present in normal cells. It is plausible that by targeting antigens with high tumor‐specificity, such as neoantigens, the likelihood of toxic effects is very limited. However, understanding the interaction between neoantigens and the host immune system remains a significant challenge. This review focuses on the potential use of neoantigen‐targeted immunotherapies in cancer treatment and the recent progress of different strategies in predicting, identifying, and validating neoantigens. Successful identification of highly tumor‐specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

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“…Systemic tumor control via the immune system can be triggered by radiation-induced changes to the tumor microenvironment as well as surrounding stromal cells [11]. The potent effects of this treatment combination have been observed in experimental studies [15,16] as well as several clinical studies for different cancer types such as brain metastases [17], head and neck squamous cell carcinoma [18], metastatic pancreatic cancer [19], lung cancer [20], and metastatic melanoma [21]. The discovery of immune checkpoint inhibitors (ICI) has led to significant advancements in immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

The Combination of Radiotherapy with Pembrolizumab in the Treatment of Metastatic Melanoma Patients: a Systematic Review

Anahid

Afra

2020

SN Compr. Clin. Med.

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Melanoma is a severe form of skin cancer arising from melanocytes. In recent years, immunotherapy in particular, immune checkpoint inhibitor (ICI), has revolutionized the treatment of metastatic melanoma. Recent studies have explored the potential of treatment of metastatic melanoma using the combination of ICI with radiotherapy (RT). In present study, we systematically review available clinical studies involving the combination of RT with pembrolizumab. A systematic search using the electronic databases including PubMed, Scopus, and Embase was conducted to retrieve relevant clinical studies investigating the use of RT+ pembrolizumab on metastatic melanoma patients. Results showed that a total of 16 studies involving 612 metastatic melanoma patients were included. Furthermore, the treatment combination was generally safe with grade 3 or higher toxicities ranging from 1 to 11%. In conclusion, this therapeutic modality is promising. However, gray areas such as limited prospective studies and optimal timing will need to be addressed in future studies.

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Metastatic Melanoma Patient Had a Complete Response with Clonal Expansion after Whole Brain Radiation and PD-1 Blockade

Cited by 44 publications

References 24 publications

Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

The Combination of Radiotherapy with Pembrolizumab in the Treatment of Metastatic Melanoma Patients: a Systematic Review

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