Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Samstein, Robert M.; Lee, Chung-Han; Shoushtari, Alexander N.; Hellmann, Matthew D.; Shen, Ronglai; Janjigian, Yelena Y.; Barron, David; Zehir, Ahmet; Jordan, Emmet; Omuro, Antonio; Kaley, Thomas; Kendall, Sviatoslav M.; Motzer, Robert J.; Hakimi, A. Ari; Voss, Martin H.; Russo, Paul; Rosenberg, Jonathan E.; Iyer, Gopa; Bochner, Bernard H.; Bajorin, Dean F.; Al‐Ahmadie, Hikmat; Chaft, Jamie E.; Rudin, Charles M.; Riely, Gregory J.; Baxi, Shrujal S.; Ho, Alan L.; Wong, Richard J.; Pfister, David G.; Wolchok, Jedd D.; Barker, Christopher A.; Gutin, Philip H.; Brennan, Cameron; Tabar, Viviane; Mellinghoff, Ingo K.; DeAngelis, Lisa M.; Ariyan, Charlotte E.; Lee, Nancy; Tap, William D.; Gounder, Mrinal M.; D’Angelo, Sandra P.; Saltz, Leonard; Stadler, Zsofia K.; Scher, Howard I.; Baselga, José; Razavi, Pedram; Klebanoff, Christopher A.; Yaeger, Rona; Segal, Neil H.; Ku, Geoffrey Yuyat; DeMatteo, Ronald P.; Ladanyi, Marc; Rizvi, Naiyer A.; Berger, Michael F.; Riaz, Nadeem; Solit, David B.; Chan, Timothy A.; Morris, Luc G.T.

doi:10.1038/s41588-018-0312-8

Cited by 3,103 publications

(3,116 citation statements)

References 35 publications

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“…TMB was considered high if ≥10 mutations/megabase were detected. This threshold was calculated based on Caris Life Sciences' cohort of 148 salivary gland carcinomas using the 80th percentile cutoff value as recently suggested by Samstein et al…”

Section: Methodsmentioning

confidence: 99%

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

et al. 2019

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Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy, which often presents at an advanced stage. A proportion of SDC are characterized by HER2 amplification and/or overexpression of androgen receptor (AR), which could be targeted in a subset of patients, but the presence of AR splice variant‐7 (AR‐V7) in some SDC cases could result in resistance to anti‐androgen therapy. We evaluated a cohort of 28 cases of SDC for potentially targetable biomarkers and pathways using immunohistochemistry (IHC) and next‐generation sequencing (DNA and RNA) assays. Pathogenic genetic aberrations were found in all but 1 case and affected TP53 (n = 19), HRAS (n = 7), PIK3CA, ERBB2 (HER2), and NF1 (n = 5 each); KMT2C (MLL3) and PTEN (n = 3 each); BRAF (p.V600E), KDM5C and NOTCH1 (n = 2 each). Androgen receptor was expressed in all cases and 13 of 27 harbored the AR‐V7 splice variant (including a case without any other detectable genetic alteration). HER2 IHC was expressed in 11 of 28 cases. The majority of SDC cases had no biomarkers predictive of immunotherapy response: 5 cases exhibited low (1%‐8%) programmed death ligand 1 (PD‐L1) expression in tumor cells, 2 cases exhibited elevated TMB, and no samples exhibited microsatellite instability. Notably, the pre‐treatment biopsies from 2 patients with metastatic disease, who demonstrated clinical responses to anti‐androgen therapy, showed AR expression and no AR splice variants. We conclude that comprehensive molecular profiling of SDCs can guide the selection of patients for targeted therapies involving AR, HER2, PD‐L1, mitogen‐activated protein kinase, and PIK3CA pathways.

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Section: Methodsmentioning

confidence: 99%

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

et al. 2019

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“…Samstein et al recently found that checkpoint inhibitors were more likely to halt tumour growth in patients with a higher number of mutations than in those with fewer mutations . The authors proposed that the tumour neoantigens generated an immune reaction.…”

Section: Rationale For An Off‐label Low‐dose Ici Therapy For Advancementioning

confidence: 99%

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Bakács¹,

Moss²,

Kleef³

et al. 2019

Scand J Immunol

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As a result of the cancer immunotherapy revolution, more than 2000 immuno‐oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co‐inhibitory signals. Unfortunately, manipulation of the co‐inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune‐related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA‐4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self‐tissues. The irAEs are very similar to that of a chronic graft‐versus‐host‐disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft‐versus‐malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto‐GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune‐suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof‐of‐principle of a low‐dose‐combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.

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“…Despite regulatory approval of immune checkpoint inhibitors in a diverse range of human solid malignancies, it remains the case that most patients do not benefit from current cancer immunotherapies. This is particularly true for patients with modestly mutated cancers arising from epithelial organs, collectively the leading causes of adult cancer‐related deaths . Detailed immune monitoring studies of exceptional patient responders to immunotherapy have revealed three critical variables that simultaneously must be satisfied for cancer regression to occur .…”

Section: Introductionmentioning

confidence: 99%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

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237

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Cited by 3,103 publications

References 35 publications

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

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