JITC Editor Picks
Elham Beyranvand Nejad, Camilla Labrie, Ziena Abdulrahman, Marit J van Elsas, Eva Rademaker, Jan Willem Kleinovink, Tetje C van der Sluis, Suzanne van Duikeren, Amina F A.S Teunisse, Aart G Jochemsen, Jan Oosting, Noel F C C de Miranda, Thorbald Van Hall, Ramon Arens, Sjoerd H van der Burg
Journal for ImmunoTherapy of Cancer 2020;8:e001326 (1 September 2020)
Research
Summary:
Several mechanisms have been described for immunotherapy resistance, including low antigen load, antigen processing and presentation defects, T cell exclusion, and an immunosuppressive tumor microenvironment characterized by an abundance of myeloid suppressor cells, regulatory T cells, and expression of immune checkpoints. Using a mouse model of local tumor recurrence and resistance following vaccine-induced regression, Elham Beyranvand Nejad and colleagues demonstrate an important role for myeloid cell infiltration in response to immunotherapy. In mice with established TC-1 tumors, therapeutic subcutaneous vaccination at the base of the tail with the human papillomavirus E743-77 synthetic long peptide and the toll-like receptor 9 agonist CpG is curative, whereas vaccination in the contralateral flank induces initial regression followed by recurrence. Antigen expression was maintained, and although almost all intratumoral CD8+ T cells expressed PD-1, recurrence could not be prevented by checkpoint blockade at any time-point. Leucocyte infiltration within recurrent tumors was reduced and altered in composition with almost no CD8+ T cells and an increased percentage of type 1 cytokine-producing CD4+ T cells. Cytoplasmic and nuclear beta-catenin expression was roughly twofold higher in the stroma of recurrent tumors and TGF-beta expression was increased in cells surrounding the tumor. The composition of intratumoral myeloid cells was shifted away from inflammatory (Ly6Chigh) MHC class II+ myeloid cells, tumor associated macrophages (Ly6Clow cells) and neutrophils (Ly6G+) in regressed tumors in favor of non-inflammatory Ly6ClowF4/80hi/low cells in recurrent tumors. Notably, recurrent TC-1 tumor cells isolated at the time of the relapse did not respond to vaccination when injected into naïve hosts. Tumors originating from reinjected recurrent tumor cells had low numbers of CD45+ tumor-infiltrating leukocytes and dramatically reduced myeloid cell content, including fewer CD11b+, matured (MHC class II+) and inflammatory (Ly6Chigh) cells, as well as CD11b+F4/80+iNos+ (M1-type) macrophages and plasmacytoid dendritic cells. When combined with cisplatin, however, vaccination led to an increased CD45+ immune cell infiltration in the reinjected TC-1 recurrent tumors, with full regression in the majority of mice and significantly improved survival. This finding further emphasizes the importance of tumor-infiltrating innate immune cells during immunotherapy.
Francesca Zammarchi, Karin Havenith, Francois Bertelli, Balakumar Vijayakrishnan, Simon Chivers, Patrick H van Berkel
Journal for ImmunoTherapy of Cancer 2020;8:e000860 (10 September 2020)
Research
Summary:
Regulatory T cells (Tregs) play key roles in generating an immunosuppressive tumor microenvironment, and attempts to deplete or block Tregs for cancer immunotherapy have had limited success. Francesca Zammarchi et al reasoned that camidanlumab tesirine, an anti-CD25 antibody-drug conjugate with activity against lymphoma, may have antitumor activity through depletion of CD25-expressing Tregs. Because the antibody component of camidanlumab tesirine does not cross react with mouse CD25, Zammarchi and colleagues generated an anti-murine CD25-ADC by conjugating the well-defined rat mAb PC61 to tesirine. In two syngeneic models of CD25-negative colon cancer (MC38 and CT26), CD25-ADC had strong, dose-dependent, and durable antitumor activity against established tumors. Furthermore, strong synergy was observed for suboptimal doses of CD25-ADC combined with anti-PD-1 antibody. New tumors did not develop upon rechallenge after CD25-ADC monotherapy or in combination with anti-PD-1. The activity of CD25-ADC required CD8+ T cells. In longitudinal T cell immunophenotype studies, one single dose of CD25-ADC, either alone or in combination with anti-PD-1, led to robust and durable depletion of intratumoral Tregs through 11 days after administration, while maintaining levels of CD8+ effector T cells. CD25-ADC treatment also reduced the number of circulating Tregs, but the effect was not durable, with values returning to control levels by day 11 post dose. Circulating CD8+ effector T cell levels were not affected by CD25-ADC treatment. No significant body weight loss or clinical observations were recorded in any treatment group. A phase I trial (NCT03621982) of camidanlumab tesirine in patients with selected advanced solid tumors is ongoing.
Andrea Schmidts, Leah C Marsh, Ambike A Srivastava, Amanda A Bouffard, Angela C Boroughs, Irene Scarfò, Rebecca C Larson, Felipe Bedoya, Bryan D Choi, Matthew J Frigault, Stefanie R Bailey, Mark B Leick, Sonika Vatsa, Michael C Kann, Michelle S Prew, Benjamin P Kleinstiver, J Keith Joung, Marcela V Maus
Journal for ImmunoTherapy of Cancer 2020;8:e000990 (7 September 2020)
Research
Summary:
High manufacturing costs and variable yields is a major barrier to broader use of engineered T cell therapies. To improve over traditional manufacturing approaches making use of soluble or bead-bound antibodies against CD3 and CD28 along with IL-2 to activate CAR T cells, Andrea Schmidts et al developed artificial antigen presenting cells (aAPCs) with genetically encoded T cell stimulation and costimulation as well as disrupted expression of the low-density lipoprotein receptor to prevent lentiviral entry. The transduction efficiency of a second generation 4-1BB-based CAR (akin to one of the approved products) into primary human T cells was nearly equivalent for aAPCs compared to the bead approach and CD8+ T cells were preferentially expanded over CD4+ T cells. Target cell lysis in vitro was effectively identical between CAR T cells generated with aAPCs and bead-based approaches, and comparable levels of antigen-specific interferon gamma production was observed in culture supernatants. In vivo, the aAPC-generated CAR T cells effectively cleared high tumor burdens in a xenograft mouse model of acute lymphoblastic leukemia. Notably, when using peripheral blood mononuclear cells containing, on average, 11% monocytes, as starting material, transduction efficiency for the CAR was twofold higher with the aAPCs compared to beads, resulted in a twofold higher yield. The findings merit further investigation of aAPCs as an “off-the shelf” simple more cost-efficient manufacturing procedure for CAR T cells.
Joshua E Reuss, Valsamo Anagnostou, Tricia R Cottrell, Kellie N Smith, Franco Verde, Marianna Zahurak, Mara Lanis, Joseph C Murray, Hok Yee Chan, Caroline McCarthy, Daphne Wang, James R White, Stephen Yang, Richard Battafarano, Stephen Broderick, Errol Bush, Malcolm Brock, Jinny Ha, David Jones, Taha Merghoub, Janis Taube, Victor E Velculescu, Gary Rosner, Peter Illei, Drew M Pardoll, Suzanne Topalian, Jarushka Naidoo, Ben Levy, Matthew Hellmann, Julie R Brahmer, Jamie E Chaft, Patrick M Forde
Journal for ImmunoTherapy of Cancer 2020;8:e001282 (13 September 2020)
Research
Summary:
Relapse is common after curative-intent surgery for resectable non-small cell lung cancer and prognosis for recurrent disease is very poor. Previously, Joshua E Reuss and colleagues found neoadjuvant nivolumab monotherapy to be safe and feasible for patients with resectable non-small cell lung cancer (NSCLC). Based on an encouraging rate of pathologic response with monotherapy and promising data for combined PD-1 and CTLA-4 blockade in advanced NSCLC, the study was expanded to include an arm investigating neoadjuvant nivolumab plus ipilimumab. The study was terminated early by investigator consensus after a total of nine patients were enrolled. All patients received all scheduled doses of therapy and were fit for planned surgery, yet six (67%) experienced treatment-related adverse events, which were grade 3 or greater in three (33%) participants. One patient experienced grade 5 acute respiratory distress syndrome (ARDS) after resection, although given the timing and setting of complicated surgery, the fatal ARDS was deemed likely to have resulted from postoperative complications unrelated to study treatment. Among the six patients who underwent resection, two had tumor pathologic complete responses and continued to remain disease-free for more than 24 months after surgery. Pathologic response was significantly associated with pre-treatment tumor PD-L1 expression but not tumor mutational burden. Although the long-term disease-free status for a subset of patients is encouraging, given the toxicity profile, the study highlights a need for the identification of predictive biomarkers that enrich for response for future trials of dual immunotherapy in the neoadjuvant setting.
Joe-Marc Chauvin, Hassane M Zarour
Journal for ImmunoTherapy of Cancer 2020;8:e000957 (7 September 2020)
Research
Summary:
T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is expressed in activated T cells, natural killer cells, and regulatory T cells and its two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), are expressed by both tumor cells and antigen-presenting cells in the tumor microenvironment. Potent inhibition of both innate and immune cells through the receptor has been demonstrated both in vivo and in vitro, evidence which Joe-Marc Chauvin and Hassane M Zarour describe in detail to make the case for further development of anti-TIGIT immunotherapies. In both pre-clinical models and human patients, TIGIT blockade synergizes with anti-PD-(L)1 therapy to directly enhance tumor-specific CD8+ T cell proliferation and effector function. TIGIT blockade also potentiates NK cell antitumor activity, and emerging evidence suggests some NK cell-mediated helper activity in augmenting CD8+ T cell responses after anti-TIGIT therapy. Several escape mechanisms for TIGIT/PD-1 blockade have been identified, including downregulation of DNAM-1 (CD226) in the tumor microenvironment, and the review proposes novel combinatorial strategies to potentiate the effectiveness of future anti-TIGIT approaches.