The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Clinical /Translational Cancer Immunotherapy Co-Section Editor, James Gulley, MD, PhD, FACP.
“Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients” by Sultan Al-Jawad et al
While there has been much deliberation in the oncology community on how to treat patients with cancer who become infected with SARS-CoV-2, there has been little evidence thus far to inform important clinical decisions. Sultan Abdul-Jawad and colleagues initiated the SOAP (Sars-CoV-2 fOr cAncer Patients) study in combination with a COVID-ImmunoPhenotyping (COVID-IP) study too assess immunological effects of SARS-CoV-2 infection in patients with cancer. Among the 41 patients in the cohort, the 18 with hematological cancers were enriched for increased severity of COVID-19 symptoms and almost double the median duration of viral shedding (as detected by nasopharyngeal swab) compared to the 23 patients with solid tumors. Additionally, while lymphocyte counts were decreased during active COVID-19 across cohorts, those with hematologic cancers displayed prolonged dysregulations in blood parameters, unlike the group with solid tumors where baseline values were re-established within 4 to 6 weeks after resolution of symptoms. Deep immune profiling including 175 flow cytometry parameters and 22 cytokines recapitulated previously described inflammatory signatures associated with COVID-19, included elevated levels of IL-6, IL-8, IL-10 and IP-10. A strong, yet transient COVID-19 immune signature characterized by exaggerated elevation of IL-6/IL-10 and decreased levels of defined B, T, NK, and DC subsets was seen in the solid tumor cohort. Patients with solid tumors also had decreased CD8+ and CD4+ T cell counts with increased activation and exhaustion markers compared to non-cancer patients—this T cell exhaustion was even more pronounced among those with hematologic malignancies. Analysis of humoral immunity showed that, despite decreased B cell counts, roughly 75% of cancer patients developed IgG and/or IgM antibodies against SARS-CoV-2 spike protein. However, seroconversion was slower and less frequent for patients with hematological malignancies compared to those with solid tumors. Altogether, these findings indicate that patients with hematological malignancies may experience immune dysregulation after SARS-CoV-2 infection, including T cell exhaustion, reduced viral clearance and compromised humoral immunity—possibly necessitating special considerations for providing therapy, quarantining/isolation, vaccinations and more.
“Therapy of established tumors with rationally designed multiple agents targeting diverse immune–tumor interactions: engage, expand, enable” by Kellsye P. Fabian et al
While the strategies needed to successfully use immunotherapy to treat non-immunogenic tumors are complex, targeted pre-clinical models are gaining traction. As Kellsye Fabian and colleagues describe, such strategies require a multi-pronged approach to “engage,” “expand,” and “enable” the anti-tumor immune response. To do this, they investigated a combination pentatherapy in a murine colon cancer model, where transgenic mice expressing carcinoembryonic antigen (CEA), which is often overexpressed in colorectal cancer, were implanted with CEA-expressing colon carcinoma cells (MC38-CEA). In the model, a CEA-targeting adenovirus-based vaccine (Ad-CEA) with N-803, an IL15 superagonist resulted in prolonged survival and increased CD8+ and CD4+ T cell expression of costimulatory molecules OX40 and glucocortico-induced TNFR-related protein (GITR). The addition of OX40 and GITR agonists and an indoleamine-2,3-deoxygenase (IDO; an immunosuppressive enzyme) inhibitor for a pentatherapy regimen resulted in significantly reduced tumor size and a 90% cure rate for small tumors with no signs of toxicity. When comparing the pentatherapy to the respective mono, doublet, triplet, and quadruplet combinations (with Ad-CEA and N-803 being administered together), the reduction in tumor size was not linearly correlated to the number of agents, but required all five agents, emphasizing the importance of the cooperative and specific functions of every agent used. Flow cytometry and immunofluorescence analyses showed increased CD8+ T cell proliferation in peripheral blood as well as enhanced tumoral infiltration, including CEA-specific CD8+ T cells. Abundances of CD4+ memory T cells were also increased along with dampened Treg responses. The pentatherapy also proved effective in models of CEA-expressing breast and lung tumors. Overall, the results of this study are encouraging for the potential of immunotherapy to be expanded in non-immunogenic tumors and underlines the need for strategic combination strategies.
“Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer” by Sri Krishna et al
Recent studies have shown that adoptive T cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TILs) can produce complete and durable responses in a subset of patients with different cancers, however the T cell phenotypes inducing a response or lack thereof remained unknown. Beginning with single-cell mass cytometry analysis of infusion product TILs, Sri Krishna and colleagues identified a memory-progenitor stem-like T cell population enriched in infusion products that led to complete response (CR), as well as a terminally differentiated subset associated with progression post-ACT. Hierarchical clustering revealed a population of CD8+ T cell infusion products with low expression of the exhaustion marker CD39 and the activation marker CD69 (CD39-/CD69-) that also had high expression of CD44, CD27, and CD28, and low expression of TIM3. These memory-progenitor stem-like CD39-/CD69- were significantly enriched in infusion products that led to CRs in multiple cohorts. Conversely, a CD39+/CD69+ population that had lower expression of CD44, CD27, and CD28 trended higher T cell products that did not lead to response. These cell surface phenotypes were independently confirmed using multifactorial flow cytometry, and enrichment of CD39-/CD69- TILs was associated with improved progression-free survival. Transcriptomic and epigenetic profile analyses revealed a quiescent stem-like signature in CD39-/CD69- cells, which expanded and differentiated in vitro, while CD39+/CD69+ cells had the gene signature and in vitro phenotypes of terminally differentiated activated T cells. In line with previous reports that neoantigen-specific CD8+ T cells are almost exclusively CD39+, the overall abundance of HLA-neoantigen tetramer+ TILs was highest in the CD39+/CD69+ population. However, subset analyses showed that CD39-/CD69- neoantigen-specific TILs were significantly more likely to be found and more highly abundant in infusion products that led to CR. Furthermore, CD39-/CD69- neoantigen-specific TILs persisted up to 75 months post-ACT in one patient with CR patient, whereas neoantigen TCR clones declined quickly post-ACT in a patient with non-responsive disease. These findings could be harnessed to produce more robust and prolonged therapeutic responses through expansion or engineering of CD39-/CD69- TILs pre-infusion, and also add insight into T cell responses for other immunotherapies.
“TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers” by Nisha B. Nagarsheth et al
Despite the remarkable response rates seen with adoptive T cell therapies for the treatment of relapsed hematologic malignancies, limited benefit has been demonstrated to date in solid tumor settings. Providing proof of concept that cell therapy may be safe and efficacious in patients with solid tumors, Nisha B Nagarsheth at al conducted a first-in human clinical trial of T cells engineered with a receptor targeting the human papilloma virus (HPV) antigen HPV-16 E7 for metastatic HPV-associated cancers. Of the 12 patients enrolled, objective responses by RECIST were seen in half (n = 6), and one quarter (n = 3) had complete regressions of the primary tumors. The study population included eight patients with anti-PD-1 refractory disease, four of whom were among those with responses to the T cell therapy. Only one dose-limiting toxicity was observed, leading to a recommended phase II dose of 1 × 1011 cells, along with a protocol modification to prohibit infusion if a patient is hypoxic. Notably, cytokine release syndrome did not limit the dose of the engineered T cells—the most common grade 3 and 4 toxicities were determined to be related to the conditioning regimen, which included a course of IL-2 (aldesleukin). The engineered T cells persisted in peripheral blood, and anti T cell antibodies were not detected. Expression of checkpoint proteins did not correlate with response (or lack thereof) to treatments. However, transcriptomics and whole exome sequencing of tumor samples in patients with progressive disease revealed multiple mechanisms of resistance to therapy, including an inactivating mutation within HLA-A*201 (which presents HPV-16 E7), biallelic loss of B2M (a key component of the engineered T cell receptor target), and acquired defects in antigen processing as well as interferon gamma response. The study shows that adoptive cell therapy may be feasible, safe, and effective for solid tumors, while revealing a role for immune editing in treatment resistance.
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