The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Case Reports Section Editor Dr. Sebastian Kobold.
JITC’S READING LIST SUMMARIES – JANUARY 2023
“Glofitamab for relapsed or refractory diffuse large B cell lymphoma” by Michael J Dickinson et al
NEJM (2022)
Prognosis is poor for patients with diffuse large B cell lymphoma (DLBCL) who have received at least two prior lines of therapy, and although multiple CAR T cell products are approved in this setting, not all patients are able to receive treatment due to logistical, manufacturing, or resource constraints. In the phase II portion of a phase I/II study, Michael J Dickinson et al demonstrate meaningful clinical benefit with a CD20 x CD3 bispecific antibody, glofitamab, for the treatment of patients with relapsed or refractory DLBCL who had received at least two lines of therapy previously. Glofitamab has a unique binding configuration that is bivalent for CD20 and monovalent for CD3 conferring a ratio of 2 target B cells per redirected T cell. A total of 155 patients were enrolled and 154 received at least one dose of the study treatment. Patients had received a median of 3 prior lines of therapy with 33% having previously been treated with CAR T cell therapy. At a median follow up of 12.6 months, 39% of the 155 enrolled patients had a complete response and response rates were among 52 patients with prior CAR T cell therapy. The median time to a complete response was 42 days and at data cutoff, 66% of objective responses (53 of 80 patients) and 80% of complete responses (49 of 61 patients) were ongoing. All patients received a pretreatment run-in of 7 days of obinutuzumab to mitigate cytokine release syndrome, and 63% of patients experienced this adverse event, with the vast majority being low-grade. Grade 3 or higher cytokine release syndrome occurred in 4% of patients.
Why this matters: Despite regulatory approvals, CAR T cell therapies are unavailable for many patients with relapsed or refractory diffuse large B cell lymphoma. These data demonstrate that the CD20 x CD3 bispecific glofitamab is an active therapy for diffuse large B cell lymphoma that offers durable responses with manageable toxicity, even in patients with prior CAR T cell therapy.
“PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program” by Masao Hashimoto et al
Nature (2022)
Using murine models of chronic lymphocytic choriomeningitis virus (LCMV) infection, Masao Hashimoto et al elucidated molecular mechanisms of synergy between PD-1 inhibitors and IL-2. Adoptive transfer experiments demonstrated that viral control with combination anti-PD-1 plus IL-2 treatment as well as both single agent therapies were all entirely mediated by PD-1+ stem-like CD8+ T cells, with minimal to no response from the more differentiated populations. At both the RNA and protein levels, combination treatment and IL-2 resulted in downregulation of exhaustion signatures and upregulation of acute effector and memory programs in LCMV-specific CD8+ T cells compared to anti-PD-1 alone. Furthermore, combination treatment or IL-2 monotherapy resulted in superior effector function, as well as the ability to produce interferon gamma even in the absence of cognate antigen. Combination therapy resulted in favorable epigenetic changes to the LCMV-specific CD8+ T cell populations toward chromatin states resembling functional CD8+ T cells following an acute infection, including increased accessibility of chemokine and cytokine response and effector genes. Interestingly, sequential treatment experiments demonstrated that while IL-2 monotherapy was sufficient to expand virus-specific CD8+ T cells, the addition of anti-PD-1 was necessary to effectively reduce viral load, potentially mediated by the favorable CD8+ Teff cell/CD4+ Treg ratio produced by the combination. Importantly, CD25 engagement by IL-2 was essential for the synergistic effects of combination therapy, as anti-CD25 blocking antibodies and use of an IL-2 variant that does not bind CD25 both substantially decreased LCMV-specific CD8+ T cell expansion.
Why this matters: There is substantial interest in developing IL-2 in combination with anti-PD-1 for the treatment of cancer. These data provide valuable insight into the cell populations and programs that are responsible for control of chronic viral infections with IL-2/anti-PD-1 combination, which may inform future drug development strategies for cancer.
“Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma” by Maartje W Rohaan et al
NEJM (2022)
Randomized data to inform the optimal subsequent-line therapy for patients with advanced melanoma that progresses after anti-PD-1 are lacking. In a randomized, multicenter, open-label phase III trial, Maartje W Rohann et al compared a single adoptive transfer of 5x109 to 2x1011 TILs (preceded by cyclophosphamide and fludarabine and followed by high-dose IL-2) versus ipilimumab (3mg/kg every 3 weeks for up to 4 doses) for 168 patients with unresectable or metastatic stage IIIC or IV cutaneous melanoma. Randomization was stratified by BRAFV600 mutation status, treatment line (first- versus second-line), and center. Among all randomized patients, 24% and 62% had disease progression following adjuvant and first-line anti-PD-1 therapy, respectively. Median progression-free survival according to RECISTv1.1, the study’s primary endpoint, was significantly longer for the TIL arm (7.2 months) versus the ipilimumab arm (3.1 months; HR 0.50, p<0.001)—a difference that remained significant when using the immune-related response criteria (HR 0.56; 95% CI 0.39 to 0.79). Objective and complete response rates also favored the TIL arm (ORR 49% versus 21%; CR 20% versus 7%). Median overall survival, a secondary study endpoint, was 25.8 versus 18.9 months for patients who received TIL versus ipilimumab, respectively (HR 0.83; 95% CI 0.54 to 1.27). Treatment-related adverse events of grade 3 or higher occurred in 100% and 57% of patients in the TIL and ipilimumab groups, respectively, with one death in the TIL arm considered to be unrelated to treatment. Global health-related quality-of life, physical functioning, and emotional functioning was improved in the TIL group compared to the ipilimumab group.
Why this matters: This trial demonstrated high response rates and prolonged survival with TIL therapy for advanced melanoma, despite 86% of patients having prior anti-PD-1 exposure. TIL therapy could become an important option for patients with melanoma that progresses on anti-PD-1.
“Dendritic cells direct circadian anti-tumor immune responses” by Chen Wang et al
Nature (2022)
While it is known that both immune cells and cancer cells are regulated by circadian rhythms, whether time-dependent effects alter endogenous antitumor immunity or the efficacy of immunotherapy treatments is an open question. Using several different mouse xenograft cancer models, Chen Wang and colleagues showed a significant difference in established tumor size depending on the time of day when seeding tumor cells were engrafted. Strikingly, both adaptive and innate immune cells were necessary for the time-dependent effects on tumor growth. Additionally, tumor antigen-specific responses by CD8+ T cells and antigen presenting cells were higher for tumors engrafted during the day compared at night. Time of engraftment dependent effects on tumor volume were not observed in mice harboring tissue-specific deletions of the clock gene, Bmall, in T cells or dendritic cells, and clock-dependent activity in dendritic cells regulated antigen-specific CD8+ T cell responses. In vitro, rhythmic binding of BMAL1 to the Cd80 promoter in dendritic cells was observed, which corresponded to cyclical regulation of T cell proliferation. Anti-tumor immune response to OVA vaccination in mice engrafted with B16-F10-OVA melanoma cells was also time of day dependent.
Why this matters: Circadian rhythms of cancer cells and immune cells have largely been ignored in both pre-clinical and clinical studies of cancer therapies. This study indicates that time of day dependent mechanisms should be considered not only in the development of immunotherapies, but any therapy that may alter the immune response in any way.