Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers.

Circulating T cells from peripheral blood (PBL) can provide a rich and noninvasive source for antitumor T cells. By single-cell transcriptomic profiling of 36 neoantigen-specific T cell clones from 6 metastatic cancer patients, we report the transcriptional and cell surface signatures of antitumor PBL-derived CD8+ T cells (NeoTCRPBL). Comparison of tumor-infiltrating lymphocyte (TIL)- and PBL-neoantigen-specific T cells revealed that NeoTCRPBL T cells are low in frequency and display less-dysfunctional memory phenotypes relative to their TIL counterparts. Analysis of 100 antitumor TCR clonotypes indicates that most NeoTCRPBL populations target the same neoantigens as TILs. However, NeoTCRPBL TCR repertoire is only partially shared with TIL. Prediction and testing of NeoTCRPBL signature-derived TCRs from PBL of 6 prospective patients demonstrate high enrichment of clonotypes targeting tumor mutations, a viral oncogene, and patient-derived tumor. Thus, the NeoTCRPBL signature provides an alternative source for identifying antitumor T cells from PBL of cancer patients, enabling immune monitoring and immunotherapies.

ONCOS-102: A Step Forward or Sideways?

Treatment of anti-PD-1 refractory melanoma remains a challenge. Intratumoral injection of ONCOS-102, a chimeric oncolytic adenovirus expressing GMCSF, into anti-PD-1-resistant melanoma with administration of pembrolizumab was safe and effective. Response to therapy was associated with increased lymphocyte infiltration and expression of cytotoxicity and costimulatory genes. See related article by Shoushtari et al., p. 100.

Neoantigen Identification and Response to Adoptive Cell Transfer in Anti-PD-1 Naïve and Experienced Patients with Metastatic Melanoma.

PURPOSE: Immune checkpoint blockade (ICB) agents and adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) are prominent immunotherapies used for the treatment of advanced melanoma. Both therapies rely on activation of lymphocytes that target shared tumor antigens or neoantigens. Recent analysis of patients with metastatic melanoma who underwent treatment with TIL ACT at the NCI demonstrated decreased responses in patients previously treated with anti-PD-1 agents. We aimed to find a basis for the difference in response rates between anti-PD-1 naïve and experienced patients. PATIENTS AND METHODS: We examined the tumor mutational burden (TMB) of resected tumors and the repertoire of neoantigens targeted by autologous TIL in a cohort of 112 anti-PD-1 naïve and 69 anti-PD-1 experienced patients. RESULTS: Anti-PD-1 naïve patients were found to possess tumors with higher TMBs (352.0 vs. 213.5, P = 0.005) and received TIL reactive with more neoantigens (2 vs. 1, P = 0.003) compared with anti-PD-1 experienced patients. Among patients treated with TIL ACT, TMB and number of neoantigens identified were higher in ACT responders than ACT nonresponders in both anti-PD-1 naïve and experienced patients. Among patients with comparable TMBs and predicted neoantigen loads, treatment products administered to anti-PD-1 naïve patients were more likely to contain T cells reactive against neoantigens than treatment products for anti-PD-1 experienced patients (2.5 vs. 1, P = 0.02). CONCLUSIONS: These results indicate that decreases in TMB and targeted neoantigens partially account for the difference in response to ACT and that additional factors likely influence responses in these patients. See related commentary by Blass and Ott, p. 2980.

Breast Cancers Are Immunogenic: Immunologic Analyses and a Phase II Pilot Clinical Trial Using Mutation-Reactive Autologous Lymphocytes.

PURPOSE: Metastatic breast cancer (mBrCa) is most often an incurable disease with only modest responses to available immunotherapies. This study investigates the immunogenicity of somatic mutations in breast cancer and explores the therapeutic efficacy in a pilot trial of mutation-reactive tumor-infiltrating lymphocytes (TILs) in patients with metastatic disease. PATIENTS AND METHODS: Forty-two patients with mBrCa refractory to previous lines of treatment underwent surgical resection of a metastatic lesion(s), isolation of TIL cultures, identification of exomic nonsynonymous tumor mutations, and immunologic screening for neoantigen reactivity. Clinically eligible patients with appropriate reactivity were enrolled into one cohort of an ongoing phase II pilot trial of adoptive cell transfer of selected neoantigen-reactive TIL, with a short course of pembrolizumab (ClinicalTrials.gov identifier: NCT01174121). RESULTS: TILs were isolated and grown in culture from the resected lesions of all 42 patients with mBrCa, and a median number of 112 (range: 6-563) nonsynonymous mutations per patient were identified. Twenty-eight of 42 (67%) patients contained TIL that recognized at least one immunogenic somatic mutation (median: 3 neoantigens per patient, range: 1-11), and 13 patients demonstrated robust reactivity appropriate for adoptive transfer. Eight patients remained clinically eligible for treatment, and six patients were enrolled on a protocol of adoptive cell transfer of enriched neoantigen-specific TIL, in combination with pembrolizumab (≤ 4 doses). Objective tumor regression was noted in three patients, including one complete response (now ongoing over 5.5 years) and two partial responses (6 and 10 months). CONCLUSION: Most patients with breast cancer generated a natural immune response targeting the expressed products of their cancer mutations. Adoptive transfer of TIL is a highly personalized experimental option for patients with mBrCa shown to be capable of mediating objective responses in this pilot trial and deserves further study.

Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers.

The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.

Pancreatic resections: 30 and 90-day outcomes in octogenarians.

BACKGROUND: Pancreatic tumors are frequently found in a geriatric population. Given that the median age of patients with pancreatic cancer is 70 years at diagnosis and the ubiquity of CT and MRI imaging has increased the detection of pancreas masses, pancreatic surgeons often find themselves operating on patients of advanced age. This study sought to evaluate the outcomes of pancreatic resection in an octogenarian population at a single institution with a dedicated surgical oncology team. STUDY DESIGN: A retrospective chart review was performed for all patients undergoing pancreatic resection over a 13-year period at an academic community cancer center. Patient characteristics and operative outcomes were compared between patients aged 80 and older, and those younger than 80. Student t-tests, Fisher's exact test, and Kruskal-Wallis tests were used for univariate analyses. RESULTS: Over the 13-year period, a total of 48 patients of 403 undergoing pancreatic resections were aged 80 or older. Of these 48 patients, 35 underwent pancreaticoduodenectomy (Whipple) and 13 underwent distal pancreatectomy. Patient characteristics including ASA classification were similar among the two age groups. The procedures themselves were equally complicated with similar operative times, transfusion requirements, estimated blood losses, and portal vein resections. The number and severity of complications such as delayed gastric emptying and pancreatic leak were not statistically different between the two groups. Additionally, the 30-day reoperation, readmission, and mortality rates were not statistically different. Outcomes at 90-days revealed an increased rate of readmission amongst octogenarians who underwent Whipple without an increase in rates of major complications. The total number of deaths in the octogenarian group was 3 (6.2%) vs. 6 (1.7%) in the non-octogenarian group (p = 0.080). The median length of stay was similar amongst the two age groups. CONCLUSIONS: At a large-volume academic community cancer center with a dedicated surgical oncology team, highly selected octogenarians can undergo pancreatic resection safely with outcomes that do not differ significantly from their younger counterparts.

Ureteral stents increase risk of postoperative acute kidney injury following colorectal surgery.

BACKGROUND: Ureteral stents are commonly placed before colorectal resection to assist in identification of ureters and prevent injury. Acute kidney injury (AKI) is a common cause of morbidity and increased cost following colorectal surgery. Although previously associated with reflex anuria, prophylactic stents have not been found to increase AKI. We sought to determine the impact of ureteral stents on the incidence of AKI following colorectal surgery. METHODS: All patients undergoing colon or rectal resection at a single institution between 2005 and 2015 were reviewed using American College of Surgeons National Surgical Quality Improvement Program dataset. AKI was defined as a rise in serum creatinine to ≥ 1.5 times the preoperative value. Univariate and multivariate regression analyses were performed to identify independent predictors of AKI. RESULTS: 2910 patients underwent colorectal resection. Prophylactic ureteral stents were placed in 129 patients (4.6%). Postoperative AKI occurred in 335 (11.5%) patients during their hospitalization. The stent group demonstrated increased AKI incidence (32.6% vs. 10.5%; p < 0.0001) with bilateral having a higher rate than unilateral stents. Hospital costs were higher in the stent group ($23,629 vs. $16,091; p < 0.0001), and patients with bilateral stents had the highest costs. Multivariable logistic regression identified predictors of AKI after colorectal surgery including age, procedure duration, and ureteral stent placement. CONCLUSIONS: Prophylactic ureteral stents independently increased AKI risk when placed prior to colorectal surgery. These data demonstrate increased morbidity and hospital costs related to usage of stents in colorectal surgery, indicating that placement should be limited to patients with highest potential benefit.

Tacrolimus for the prevention and treatment of rejection of solid organ transplants.

Since its introduction to the antirejection armamentarium in 1994, tacrolimus has become the workhorse of transplant professionals for avoidance of solid organ transplant rejection. Not only does tacrolimus have potent immunosuppressive qualities that prevent rejection, but dosing is straight forward and it is generally well tolerated. However, in the long term, conditions such as calcineurin inhibitor nephrotoxicity can become a problem. A discussion of the compound, the pharmacokinetics, history, and current approved uses for tacrolimus is described. Indeed, tacrolimus is the most important drug for preventing transplant rejection. However, the increased appreciation for significant side effects, particularly in the long term, has led to building interest in new agents with different mechanisms of action and different metabolism.