The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's co-Section Editor for the Immunotherapy Biomarkers section, Dr. Alexandra Snyder Charen.
“Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma” by Fredrick L Locke et al
Axicabtagene ciloleucel (axi-cel) is an anti-CD19 CAR T cell therapy that is currently FDA-approved for the treatment of large B cell lymphoma that is relapsed/refractory (R/R) after at least two prior lines of therapy. For patients with large B cell lymphoma that is R/R to one prior therapy, the current standard-of-care (SOC) is high-dose chemotherapy followed by autologous stem cell transplantation. Frederick L Locke and colleagues report efficacy from ZUMA-7, a phase III trial comparing second-line axi-cel to SOC for the treatment of R/R large B cell lymphoma. The primary endpoint was event-free survival (EFS). A total of 359 patients were randomized and at median-follow-up of 24.9 months, median PFS in the axi-cel group was significantly improved compared to SOC at 8.3 months (95% confidence interval [CI] 4.5 to 15.8) versus to 2.0 months (95% CI 1.6 to 2.8). At 24 months, the estimated EFS rate for patients who received axi-cel was 41% versus 16% for SOC. Median overall survival (OS) was numerically better for those treated with axi-cel (not reached vs 35.1 months; hazard ratio [HR] for death 0.73) but it was not statistically significant, and the 2-year estimated OS rates were 61% for axi-cel and 52% for SOC. However, 56% of patients treated with SOC received subsequent cell therapy, and a pre-specified sensitivity analysis to account for treatment switching found that axi-cel significantly improved survival (HR 0.58; 95% CI 0.42 to 0.81). Grade ≥ 3 adverse events occurred in 91% of patients who received axi-cel and 83% of patients receiving SOC. In patients treated with axi-cel, 92% experienced cytokine release syndrome, 6% with grade ≥ 3. Overall, axi-cel as a second-line therapy for large B cell lymphoma was safe and effective in this study, and responses were more durable than the current SOC.
Why this matters: This trial demonstrates the efficacy of using axi-cel as an earlier line of therapy than its current indication, and importantly, offers additional options to patients with large B cell lymphoma in the second-line setting.
“FDA Approval Summary: Pembrolizumab for the Treatment of Tumor Mutational Burden-High Solid Tumors” by Leigh Marcus et al
Leigh Marcus et al provide context for the accelerated approval of pembrolizumab for the treatment of tumor mutational burden-high (TMB-H), advanced, pre-treated solid tumors in June, 2020. This was the fourth tissue-agnostic approval from the Food and Drug Administration (FDA) for a cancer treatment. TMB-H is believed to be a proxy for a high tumor neoantigen load and potential susceptibility to immune checkpoint inhibition. The cutoff value of 10 mut/Mb to define TMB-H for clinical trial enrollment purposes was deliberated during multi-stakeholder meetings prior to its evaluation in prospective pan-tumor trials and eventual regulatory approval. Retrospective studies on tissue pooled from 1,772 pembrolizumab-treated patients across 12 trials and 24 tumor types demonstrated an overall response rate (ORR) of 31.4% for tumors with ≥ 175 mut/exome (which roughly corresponds to 10 mut/Mb) compared to 9.5% for tumors with lower mutational loads. The non-randomized, prospective KEYNOTE-158 study evaluated the efficacy of pembrolizumab monotherapy for pre-treated, advanced solid tumors. A prespecified cutoff of 10 mut/Mb by the FoundationOneCDx Assay was used to define TMB-H. Similar to the retrospective pooled WES analysis, patients with TMB-H tumors (n = 102) had an ORR of 29.4% versus 6.3% for patients with TMB-low tumors (n = 688). Furthermore, 66% of responders had a response lasting 24 months or longer. The FDA TMB-based approval was further supported by an absence of new safety signals and favorable post hoc PFS and OS analyses from several of the randomized WES pooled trials. The sponsor agreed to post-marketing requirements to prospectively enroll patients with rarer tumors and collect data on the appropriateness of the 10 mut/Mb cutoff point.
Why this matters: Analysis of KEYNOTE-158 and supportive WES datasets led to the fourth pan-tumor, companion diagnostic-based approval for patients with TMB-H advanced cancer.
“TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion” by Mojdeh Shakiba et al
The strength of the T cell receptor (TCR)-ligand interaction is a key determinant of the rate and frequency of naïve T cell activation. Using an elegant murine model, Modjeh Shakiba identified two distinct T cell phenotypes allowing for tumor escape depending on the strength of interaction with the cognate antigen. The system relied on tumors with single-residue substitutions within the SV40 large T antigen I (TAG), which allowed for modulation of affinity with TAG-specific TCRs on adoptively transferred T cells. In the draining lymph nodes, T cells encountering tumors with low-affinity antigens expressed lower levels of LAG3 and PD-1 compared to those that engaged with high-affinity antigens. By contrast, LAG3 and PD-1 were abundantly expressed in tumor-infiltrating lymphocytes (TILs) regardless of the strength of the TCR-antigen interaction. TILs encountering high-affinity antigens displayed defects in ERK phosphorylation despite intact calcium flux. Transcriptionally, TILs isolated from tumors with high-affinity antigens were enriched for expression of pathways associated with negative regulation of T cell activation and effector function, whereas the TILs in tumors with low-affinity antigens retained features of effector/memory states. Notably, the in vivo efficacy of adoptively transferred T cells with receptors with low affinity for the cognate tumor antigen was not better than that of exhausted TILs that encountered high-affinity antigens. Modulation of TCR affinity by CRISPR/Cas9 deletion of CD8alpha allowed for the identification of a “goldilocks zone” where T cells eliminated tumors more effectively than the parental lines in two different systems.
Why this matters: The study demonstrates that both high- and low-signal strength interactions can cause failed tumor control by T cells in vivo, which may have important implications for ongoing efforts attempting to isolate antigen-specific T cells for adoptive therapies.
“A human orthogonal IL-2 and IL-2Rbeta system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia” by Qian Zhang et al
IL-2 has a long history as an ex vivo reagent used to promote T cell survival and signaling as well as the early immunotherapy aldesleukin, which offers complete remissions to some patients with renal cell carcinoma and melanoma but also is associated with potentially life-threatening toxicity. Building on previous work generating a murine IL-2 and its receptor subunit IL-2Rbeta that does not interact with nor cause signaling through the endogenous IL-2 networks, Qian Zhang and colleagues describe the construction of an orthogonal receptor/cytokine pair for use in human cells. After several rounds of targeted mutagenesis and directed evolution, the resulting orthogonal IL-2/IL-2Rbeta system was highly specific. At concentrations exceeding the minimum effective concentration of wild-type IL-2, the orthogonal cytokine failed to support proliferation of a cutaneous T cell lymphoma cell line. Primary human T cells expressing a CD19 chimeric antigen receptor (CAR) and the orthogonal IL-2Rbeta displayed comparable STAT5 and ERK phosphorylation in response to the orthogonal IL-2 as the parent line with the native cytokine. In mouse models of human B-ALL co-treatment with orthogonal IL-2 and the orthogonal receptor-expressing CD19 T cells led to unexpected early deaths in the majority of the animals—except for those receiving the lowest dose of the orthogonal cytokine. However, the animals that survived showed marked reductions in leukemia burden. Treatment with the lowest dose of the orthogonal cytokine led to enhanced leukemia control even when the CAR T cell dose was sub-optimal. Lethality during treatment with the orthogonal IL-2 required the presence of human T cells carrying the orthogonal IL-2Rbeta, but was unaffected by the presence of an endogenous T cell receptor in the transferred cells. In mice not bearing leukemia, no lethality occurred with the administration of the CAR T cells and orthogonal cytokine, supporting a role for activated T cells in causing toxicity.
Why this matters: This impressively engineered system demonstrates robust and specific proliferation of CAR T cells in vivo to levels not previously achieved clinically. More work is needed to understand the mechanisms of toxicity associated with the dramatic proliferation after stimulation with the engineered cytokine.
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