JITC Editor Picks
Joshua R Veatch, Naina Singhi, Brenda Jesernig, Kelly G Paulson, Jonathan Zalevsky, Ernesto Iaccucci, Scott S Tykodi, Stanley R Riddell
Journal for ImmunoTherapy of Cancer 2020;8:e001591 (9 December 2020)
Research
Summary:
Tumor control after checkpoint blockade depends upon T cells specific for either neoantigens or self-antigens, and the relative contribution of each population is not known. Using a two-step enrichment process to expand peptide-stimulated T cells and select for antigen-specific clones, Joshua R Veatch and colleagues demonstrate the pre-treatment presence and on-treatment expansion of neoantigen-recognizing T cells in a patient with BRAFV600E-mutated melanoma who achieved disease control with bempegaldesleukin and nivolumab. Whole-exome sequencing revealed 279 single-nucleotide variants as possible neoantigens in addition to the BRAFV600E mutation, and 45 candidates were evaluated for T cell responses. Both CD8+ and CD4+ T cell responses were seen against mutated SLC39A14, and T cell-specific responses to additional variants were identified as well. Deep sequencing revealed a total of 54 neoantigen-specific TCRV-beta clonotypes, 32 of which were detectable in the tumor pre-treatment, making up 0.71% of the population. In unstimulated pre-treatment peripheral blood mononuclear cells, four of the clones were detected, accounting for a mere 0.005% of TCRV-beta sequences. In the first 5 days after treatment, neoantigen-specific clones expanded five-fold in the peripheral blood and then contracted to pre-treatment levels by 13 months. In the tumor, neoantigen-specific TCRV-beta sequences expanded by roughly 30%. By contrast, clonotypes specific for self-antigens (gp100, MAGE A3, TRP2, and tyrosinase) did not expand in the peripheral blood nor localize to the tumor. The results demonstrate a sophisticated enrichment method for identifying neoantigen-specific T cells, and suggest a likely role for these antigen specificities in tumor control.
Isobel Okoye, Lai Xu, Melika Motamedi, Pallavi Parashar, John W Walker, Shokrollah Elahi
Journal for ImmunoTherapy of Cancer 2020;8:e001849 (12 December 2020)
Research
Summary:
Upregulation of the TIM-3 ligand galectin-9 (Gal-9) has been linked to impaired T cell effector function in patients with HIV, but its effects in the context of cancer are unknown. Isobel Okoye et al profiled Gal-9 expression in peripheral blood and tumor-infiltrating T cells in samples from 40 patients with virus-associated solid tumors who were treated with oral valproate and avelumab in the non-randomized phase II LATENT trial. Significant upregulation of surface Gal-9 was seen on both CD4+ and CD8+ T cells in peripheral blood before the initiation of treatment. Overexpression of Gal-9 correlated with impaired effector function, including reduced IL-2, interferon gamma, and tumor necrosis factor alpha secretion across T cell subsets, and attenuated granzyme B and perforin production. Co-expression of Gal-9 with PD-1 and TIGIT was seen on CD4+ T cells and associated with reduced cytokine production. Patients with treatment-responsive disease had lower levels of Gal-9 mRNA in the tumor microenvironment, and the group with progressive disease had elevated levels of Gal-9-expressing CD8+ T cells in the peripheral blood. No differences in the patterns of Gal-9 expression were seen in natural killer (NK) cells after therapy. Intriguingly, Gal-9-expressing NK cells showed impaired granzyme B and perforin production with enhanced interferon gamma expression. In vitro, Gal-9 displayed dispersed cytosolic localization in resting T cells, and was recruited to the surface upon stimulation. The findings reveal Gal-9 as a marker of functional exhaustion in T cells and NK cells in patients with virus-associated solid tumors, opening the door for further studies to explore if preventing upregulation of the lectin on T cells may enhance checkpoint blockade efficacy.
Galam Leem, Junsik Park, Minwoo Jeon, Eui-Soon Kim, Sang Wun Kim, Yong Jae Lee, Seong Jin Choi, Baekgyu Choi, Seongyeol Park, Young Seok Ju, Inkyung Jung, Sunghoon Kim, Eui-Cheol Shin, Jung Yun Lee, Su-Hyung Park
Journal for ImmunoTherapy of Cancer 2020;8:e001650 (16 December 2020)
Research
Summary:
Ovarian cancer is poorly responsive to checkpoint blockade. To investigate the exhaustion and activation phenotypes of T cells in primary tumor and metastatic site samples from 65 patients with ovarian cancer, Galam Leem et al performed immunophenotyping via multicolor flow cytometry, RNA sequencing, and ex vivo functional restoration assays. The frequencies of PD-1+, CTLA-4+ and Tim-3+ cells were significantly higher in CD8+ tumor-infiltrating lymphocytes (TILs) compared to CD8+ cells in peripheral blood. No differences in PD-1 or CD69 expression were seen between tumor-specific CD8+ TILs and tumor-unrelated virus-specific CD8+ T cells. Significantly, higher frequencies of CD39 and CD103 expression were seen in tumor-specific CD8+ TILs compared to in the virus-specific population. Subdividing the CD39+ TILs into three categories based on PD-1 expression, the frequencies of CTLA-4+ and Tim-3+ cells were significantly elevated in the subpopulation with the highest levels of PD-1. High-PD-1 expressing cells also showed elevated Eomes and low T-bet, indicative of terminal exhaustion. Notably, a substantial proportion of these terminally exhausted (PD-1high CD39+ CD8+ TILs) also expressed 4-1BB. The 4-1BB-positive population displayed phenotypes indicative of higher degrees of proliferation (Ki-67) and exhaustion status (Tcf-1, Eomes and T-bet). No significant differences in exhaustion and proliferation status were seen between primary tumors and metastatic sites. Ex vivo, 4-1BB costimulation with an agonistic antibody combined with PD-1 blockade enhanced proliferative capacity and cytokine production in exhausted TILs. A total of 520 genes were differentially expressed between the 4-1BB-positive and -negative CD39+ TILs, and a signature comprised of 177 of these genes was correlated with better survival outcomes in an ovarian cancer cohort from The Cancer Genome Atlas. The study is the first to analyze distinct characteristics of tumor-specific exhausted CD8+ TILs, identifying a 4-1BB-expressing subpopulation that may represent a potential target for reinvigoration to enhance the efficacy of checkpoint inhibition in ovarian cancer.
Shannon K Boi, Rachael M Orlandella, Justin Tyler Gibson, William James Turbitt, Gal Wald, Lewis Thomas, Claire Buchta Rosean, Katlyn E Norris, Megan Bing, Laura Bertrand, Brett P Gross, Amani Makkouk, Dmytro Starenki, Kristine I Farag, Robert E Sorge, James A Brown, Jennifer Gordetsky, Hesham Yasin, Rohan Garje, Lakshminarayanan Nandagopal, George J Weiner, David M Lubaroff, Rebecca C Arend, Peng Li, Yousef Zakharia, Eddy Yang, Aliasger K Salem, Kenneth Nepple, Tatiana T Marquez-Lago, Lyse A Norian
Journal for ImmunoTherapy of Cancer 2020;8:e000725 (22 December 2020)
Research
Summary:
Multiple retrospective analyses have suggested that response rates to checkpoint inhibition in clinical trials positively correlate with body mass index (BMI) in some tumor types—the so called “obesity paradox” in cancer. In one of the first analyses of the impact of obesity on checkpoint inhibitor efficacy in the standard of care setting for renal cell carcinoma (RCC), Shannon K Boi and colleagues show that patients with BMI greater than the World Health Organization cutpoint of 30 kg/m2 had a median 6.5-month reduction in progression-free survival and a 12-month reduction in overall survival. Analyses of treatment-naïve CD8+ tumor-infiltrating lymphocytes (TILs) from patients with RCC showed that although activation statuses were not altered, obesity was associated with significantly reduced PD-1+CD8+ and PD-1highCD8+ populations. The altered TIL composition before treatment was recapitulated in orthotopic mouse models of RCC against a well-characterized background of diet-induced obesity. Furthermore, effector function, specifically interferon gamma secretion, was compromised in PD-1highCD8+ TILs in obese mice. The efficacy of a combination immunotherapy regimen comprised of adenovirus encoding murine TRAIL (AdTR) coadministered with the toll-like receptor 9 agonist CpG (AdTR/CpG) at day 7 post-tumor challenge plus anti-PD-1 was compromised in obese mice. Transcriptomic analyses and hierarchical clustering, however, revealed that tumors that responded to treatment clustered together regardless of obesity status—tumor control was characterized by robust expansion of intratumoral PD-1intCD8+ T cells that produced interferon gamma, tumor necrosis factor alpha and perforin. No obvious defects in T cell priming were observed in obese mice, yet significantly higher numbers of myeloid-derived suppressor cells (MDSCs) were found compared to the frequencies in lean hosts. Treatment-naïve obese mice had increased intratumoral concentrations of GM-CSF, IL-1-beta, CXCL1 and CCL2. Neutralization of IL-1 beta in addition to the combination immunotherapy regimen almost doubled the response rate in obese mice. The study comprehensively establishes mechanism whereby obesity may be detrimental to checkpoint blockade outcomes in RCC, motivating further examination of the “obesity paradox” in other settings.
Marcela V Maus, Sara Alexander, Michael R Bishop, Jennifer N Brudno, Colleen Callahan, Marco L Davila, Claudia Diamonte, Jorg Dietrich, Julie C Fitzgerald, Matthew J Frigault, Terry J Fry, Jennifer L Holter-Chakrabarty, Krishna V Komanduri, Daniel W Lee, Frederick L Locke, Shannon L Maude, Philip L McCarthy, Elena Mead, Sattva S Neelapu, Tomas G Neilan, Bianca D Santomasso, Elizabeth J Shpall, David T Teachey, Cameron J Turtle, Tom Whitehead, Stephan A Grupp
Journal for ImmunoTherapy of Cancer 2020;8:e001511 (16 December 2020)
Research
Summary:
Chimeric antigen receptor (CAR) T cell therapies may offer durable responses in patients with relapsed hematologic malignancies that formerly carried a dismal prognosis, but as “living drugs” these treatments are associated with a unique spectrum of toxicities that may be challenging to manage. To offer practical guidance for oncologists and improve outcomes for patients, the Society for Immunotherapy of Cancer convened a panel of experts in the cell therapy field to develop evidence- and consensus-based recommendations on the optimal management of clinically significant toxicities with CAR T cell therapy, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cardiotoxicity, and other important concerns such as infectious disease prophylaxis and quality of life. As one of the first clinical practice guidelines specifically devoted to toxicity management for cell therapies, and developed by a panel that included perspectives from subspecialties, nursing, and patient advocacy, this will be an invaluable resource for the hematology and oncology communities, especially as the landscape of this revolutionary class of immunotherapy continues to expand.