JITC Digest November 2021

JITC Editor Picks

Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects

Journal for ImmunoTherapy of Cancer 2021;9:e002505 (4 October 2021)
Research

Summary:

Inhibition of the chemokine CXCL12 has been demonstrated to alleviate T cell exclusion from the tumor microenvironment (TME) in preclinical models, but clinical experience with the strategy is largely limited to hematologic malignancies. Meggy Suarez-Carmona and colleagues report disease control and TME modulation with anti-CXCL12 in combination with pembrolizumab in patients with advanced stage, heavily pretreated metastatic colorectal and pancreatic cancer in the phase I/II OPERA trial (KEYNOTE-559, NCT03168139). A total of 20 patients with microsatellite stable metastatic colorectal (n = 11) or pancreatic cancer (n = 9) were enrolled and treated with twice weekly fixed dose olaptesed pegol (an anti-CXCL12 L-RNA aptamer also called NOX-A12) monotherapy for 2 weeks followed by combination therapy with 200 mg pembrolizumab every 3 weeks until disease progression or limiting toxicity. Paired needle biopsies from liver metastases were collected pre- and post-monotherapy with NOX-A12. Treatment was safe and well-tolerated. The most common adverse events were abdominal pain, fatigue and peripheral edema, and no new safety signals emerged. Although no objective responses by RECIST v1.1 were observed, 7 out of 20 patients remained on study treatment for more than 6 months and a disease control rate of 25% was observed. Lower numbers of infiltrating T cells at baseline compared to expected values in the literature were seen in the heavily pre-treated patients in the OPERA trial. Multiplex quantification of 50 cytokines, chemokines, and growth factors revealed three distinct clusters of tissue response, categorizable by the degree of IL-2, interferon-gamma and IL-16 signature versus decrease in Th1 cytokines and IL-16 and CXCL10. A unique population of CD14⁺CD15⁺ promonocytic precursor cells were identified that localized with CXCL12. The findings support future studies of the combinatorial strategy focusing on one tumor entity and including patients with fewer prior lines of treatment.

Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

Research

Summary:

Recent transcriptomic studies have identified new tissue repair and regulatory functions for the liver- and barrier tissue-localized mucosal-associated invariant T (MAIT) cells that recognize microbial riboflavin-derived antigens. To explore the potential for MAIT cells as adoptive therapies, Marie Tourret and colleagues profiled population dynamics and alloreactivity of MAIT cells in a variety of in vitro and in vivo models, including human patients post-stem cell transplant. Longitudinal peripheral blood mononuclear cells (PBMCs) samples collected from two cohorts of children and one cohort of adults who underwent allogeneic hematopoietic stem cell transplantation (HSCT) revealed gradually recovering numbers of T cells starting 1 month after transplantation and returning almost to normal levels by the 1 year mark with practically zero increase in the number of MAIT cells. Even 2 years HSCT, MAIT cell values remained five times lower than in age-matched donors. The reconstitution of MAIT cells and T cells were both impaired in patients that experienced severe acute graft versus host disease (GVHD). In vitro, MAIT cells proliferated in response to IL-15 and IL-17 but not IL-2, with higher numbers of replications when microbial metabolites were present in the culture medium. In the absence of the microbial metabolite, MAIT cells barely proliferated in response to stimulation by allogeneic cells. In murine models of xenogenic GVHD where MAIT cells were co-injected along with human PBMCs, virtually no proliferation of the MAIT cells occurred. Even when mice were co-injected with microbial metabolites or recombinant human IL-15 leading to massive expansion and infiltration of xenogenic T cells, MAIT cells were barely detectable. The findings set the stage for exploration of MAIT cells as universal donor platforms for adoptive cell therapies.

Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)

Peter Kar Han Lau, Breon Feran, Lorey Smith, Arian Lasocki, Ramyar Molania, Kortnye Smith, Alison Weppler, Christopher Angel, Damien Kee, Prachi Bhave, Belinda Lee, Richard J Young, Amir Iravani, Hanxian Aw Yeang, Ismael A Vergara, David Kok, Kate Drummond, Paul Joseph Neeson, Karen E Sheppard, Tony Papenfuss, Benjamin J Solomon, Shahneen Sandhu, Grant A McArthur
Journal for ImmunoTherapy of Cancer 2021;9:e002995 (8 October 2021)
Research

Summary:

First-line treatment with either dabrafenib plus trametinib or ipilimumab plus nivolumab is associated with intracranial response rates of roughly 50% for melanoma brain metastases, however, resistance to BRAF/MEK inhibition emerges rapidly and the impact of sequencing on efficacy of subsequent lines of therapy is not known. Peter Kar Han Lau and colleagues provide evidence that the activity of ipilimumab plus nivolumab after prior treatment with dabrafenib plus trametinib is very poor and further show that tumors that progress on BRAF/MEK inhibition exhibit gene expression profiles characteristic of resistance to anti-PD-1. At the time of the study, reimbursement requirements in Australia mandated that treatment with BRAF/MEK inhibition in the first line for BRAFV600-mutant melanoma, so the majority of patients receiving upfront ipilimumab plus nivolumab had BRAF wild-type disease. For the 25 patients in the single-center cohort who received ipilimumab plus nivolumab in the first line, the response rate was 75% compared with a response rate of only 4.8% among the 30 patients that were treated with combination immunotherapy in the second or third line after BRAF/MEK inhibition. In cases where extracranial responses could be assessed by FDG-PET, the rates were generally in line with the intracranial responses at 82.4% (14/17) and 11.1% (1/9) for first line and second/third line ipilimumab–nivolumab, respectively. RNA sequencing analysis of 18 systemic therapy-naïve tumor samples and 14 samples from tumor that progressed after BRAF/MEK inhibition derived from 29 patients revealed differential expression of genes encoding a range of structural, signaling, metabolic, and myeloid activation cellular functions as well as upregulation of monocyte and myeloid chemokines associated with tumor-associated macrophages and monocyte derived myeloid-derived suppressor cells. Also enriched in the post-progression samples was the 26 gene pathway Innate Anti-PD1 Resistance Signature (IPRES). The study offers mechanistic and clinical evidence to inform choice of immunotherapy over targeted therapy for frontline treatment of melanoma brain metastases.

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy: a prospective observational study

Summary:

Respiratory tract infections are among the most common complications after CAR T cell therapy and extremely sparse data are available on the relative efficacy and immunogenicity of vaccines to common circulating pathogens after B cell-depleting adoptive cell therapies. Carla S Walti and colleagues prospectively enrolled for observation and evaluation of antibody titers and responses a total of 18 patients undergoing treatment with CD19-, CD20-, and BCMA-directed CAR T cell therapy and eight healthy adult controls, all of whom were planning to receive the four-strain inactivated vaccine for seasonal flu. Among the five patients who received the vaccine prior to undergoing CAR T cell therapy 40% (n = 2; 95% CI 12% to 77%) had antibody responses to at least one vaccine strain. Antibody titers decreased after CAR T cell therapy infusion, but neutralizing titers to one strain remained above baseline for at least 30 days. For the 13 patients who received the flu vaccine after CAR T cell treatment, responses to at least one vaccine strain were seen in 31% of the cohort (n = 4; 95% CI 13% to 58%). Responses to at least one vaccine strain were seen at a similar rate in the healthy control participants, at a rate of 38% (n = 3). Most of the participants that did have a response to the vaccine had IgA and IgM levels below the lower limit of normal and univariate logistic regression analyses in the cohort that was vaccinated after CAR T cell treatment did not identify any associations between an antibody response and age, sex, underlying malignancy, time from CAR T cell therapy, IgG level, CD19⁺ B cell count, or CD4⁺ T cell count. The findings are one of the first reports of vaccine immunogenicity after CAR T cell therapy and support consideration for vaccination for influenza and other pathogens in patients undergoing treatment.

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