JITC Editor Picks
Benjamin A Derman, Yuanyuan Zha, Todd M Zimmerman, Rebecca Malloy, Andrzej Jakubowiak, Michael R Bishop MD, & Justin Kline.
Journal for ImmunoTherapy of Cancer 2020;8:e000286 (15 January 2020)
Regulatory (Treg) T cells rapidly reconstitute after autologous stem cell transplant (ASCT), possibly driving disease progression in multiple myeloma. Reasoning that reducing and delaying the recovery of Treg cells may enhance the anti-myeloma immune response after ASCT, Benjamin Derman and colleagues performed a randomized pilot study to evaluate two methods of Treg cell depletion in multiple myeloma patients undergoing transplants. In total, 15 patients were enrolled and randomized to one of three treatment arms. One group received anti-CD25 monoclonal antibody (basiliximab) on day +1 post-transplant for in vivo Treg depletion (IVTRD). For the ex vivo Treg depletion arm (EVTRD), anti-CD25 were used to deplete Treg cells from autologous stem cell grafts prior to transplant. No depletion was performed in the control arm. In the EVTRD arm, manipulation of autologous stem cell grafts was able to achieve a 90% depletion of Treg cells—decreasing the median relative frequency of CD25+ cells from 8.3% to 0.9%. After transplant, both IVTRD and EVTRD led to significant reductions compared to the control arm in Treg cell frequency in peripheral blood samples from patients between days +7 and +90. Although clinical outcomes were not primary endpoints in this study, all five patients in the EVTRD arm achieved stringent complete response and 4 out of 5 achieved minimal residual disease negativity by multicolor flow cytometry. The findings indicate that Treg cell depletion may enhance post-transplant anti-tumor response, warranting further investigation as a possible platform for other post-tranplant immunotherapies to improve outcomes after ASCT.
Lucine Marotte, Sylvain Simon, Virginie Vignard, Emilie Dupre, Malika Gantier, Jonathan Cruard, Jean-Baptiste Alberge, Melanie Hussong, Cecile Deleine, Jean-Marie Heslan , Jonathan Shaffer, Tiffany Beauvais, Joelle Gaschet, Emmanuel Scotet, Delphine Fradin, Anne Jarry, Tuan Nguyen, Nathalie Labarriere
Journal for ImmunoTherapy of Cancer 2020;8:e000311 (29 January 2020)
Despite advances in cell engineering and protocols for the isolation of antigen-specific cytotoxic T lymphocytes (CTLs), the feasibility of engineering CD8+ effector/memory T cells to boost their anti-tumor activities has yet to be demonstrated. By applying CRISPR/Cas9 genome editing technology to human melanoma-specific CTLs isolated using a procedure derived from the phase 1/2 MelSort clinical trial, Lucine Marotte et al. generated and characterized PD-1-deficient effector memory CD8+ T cells. In mouse models of PD-L1-positive melanoma, the engineered CTLs significantly delayed tumor growth compared to unedited CTLs expressing an identical T cell receptor. The functional avidities of wild type and PD-1 knockout melanoma-specific CTLs were similar as well as their in vitro cytotoxic properties. Notably the engineered CTLs lacking PD-1 produced less interferon gamma and IL-2 globally compared to wild-type control CTLs, which could potentially be attributed to significant overexpression of TIGIT in the edited cells. Transcriptomic analyses revealed significantly upregulated expression of metabolism-associated genes along with decreased expression of genes related to DNA replication and proliferation in the CTLs lacking PD-1. The study suggests that the use of gene-edited lymphocytes for adoptive cell therapy, potentially in conjunction with other approaches to modulate the tumor microenvironment, could improve the efficacy of immunotherapy for solid tumors.
Shibin Qu, Tejaswi Worlikar, Amy E Felsted, Anutosh Ganguly, Megan V Beems, Ryan Hubbard, Ashley L Pepple, Alicia A Kevelin, Hannah Garavaglia, Joe Dib, Mariam Toma, Hai Huang, Allan Tsung, Zhen Xu, Clifford Suhyun Cho
Journal for ImmunoTherapy of Cancer 2020;8:e000200 4 (15 January 2020)
Responsiveness to checkpoint inhibitors correlates with tumor immunogenicity. Despite ongoing efforts to use tumor-directed therapies such as thermal ablation and radiation to incite inflammation within the tumor microenvironment, these strategies have not consistently proven to augment the effectiveness of immunotherapy. Hypothesizing that the protein-denaturing effects of heat and ionizing radiation limits the immunogenicity of tumor-directed therapies, Shibin Qu et al. investigated the immunostimulatory effects of histotripsy, a non-invasive tumor ablation method that disrupts cellular architecture without heat generation through high-pressure overlapping ultrasound pulses. In mouse models of non-immunogenic melanoma, histotripsy resulted in significant increases in intratumoral CD8+ T cell infiltration in the primary tumor compared to other modalities of tumor-directed therapy. The ablation method also induced a potent abscopal effect, as significant numbers of CD8+ T cells infiltrated distant tumors after contralateral histotripsy—a response not observed after radiation therapy or radiofrequency ablation. The abscopal effect of unilateral histotripsy was associated with a significant survival advantage in mice bearing bilateral tumors. The addition of histotripsy to checkpoint inhibition led to significant increases in CD8+ T cell infiltration along with delays in tumor growth compared to untreated controls or either single treatment in mouse models of melanoma as well as a poorly immunogenic hepatocellular carcinoma. The observations indicate that histotripsy stimulates local and systemic anti-tumor immune responses that may potentiate the therapeutic efficacy of checkpoint inhibition.
Rahul Suresh, David J Barakat, Theresa Barberi, Lei Zheng, Elizabeth Jaffee, Kenneth J Pienta, Alan D Friedman
Journal for ImmunoTherapy of Cancer 2020;8:e000244 (13 January 2020)
Adoptive transfer of activated macrophages has been evaluated in cancer patients, but minimal anti-tumor efficacy has been observed. Based on observations that the transcription factor nuclear factor kappa B p50 promotes an anti-inflammatory, suppressive M2 phenotype in macrophages, characterized by reduced cytokine production and decreased T cell activation, Rahul Suresh and colleagues performed adoptive transfer of immature myeloid cells lacking p50 in mouse models of prostate and pancreatic ductal carcinoma. After expanding lineage-depleted bone marrow mononuclear cells from p50-/- mice, cultures were exposed to M-CSF-containing media for one day to generate immature myeloid cells (IMCs). In mice inoculated with HI-Myc prostate cancer, adoptive transfer of p50-/- IMC slowed tumor growth by 3-fold compared to treatment with wild-type IMC—though effects were only observed after pre-infusion conditioning with 5-fluorouracil (5-FU). In models of pancreatic ductal carcinoma, 5-FU treatment followed by p50-/- IMC slowed tumor growth in 50% of treated mice. Strikingly higher proportions of cells expressing dendritic cell markers were isolated from prostate carcinoma tumors after 5-FU treatment and adoptive transfer of p50-/- IMC compared to wild type IMC. Infusion of p50-/- IMC also increased the proportion of intratumoral CD8+ T cells by 5 fold compared to wild type IMC, and anti-tumor effects were significantly reduced by depletion of CD8+ cells. The results offer rationale for investigating the production of p50-deleted IMC from patient-derived marrow as a potential adoptive cell therapy.