The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Section Editor for the Immune Cell Therapies and Immune Cell Engineering Section, Dr. Marcela V. Maus.
“CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy” by Alba Rodriguez-Garcia et al
As adoptive cell therapy strategies against solid tumors continue to be developed, increasing efforts are being dedicated to overcoming immunosuppressive tumor microenvironments (TMEs). Tumor associated macrophages (TAMs) can have anti-tumor/pro-inflammatory (M1) or tumor promoting/anti-inflammatory (M2) phenotypes. In a murine ovarian cancer model, Alba Rodriguez-Garcia and colleagues first isolated and characterized TAMs and found folate receptor β (FRβ)-expressing TAMs shared morphological, transcriptional, and metabolic M2 TAM phenotypes. Further, FRβ+ TAMs impaired antigen-specific CAR T cell proliferation and interferon-gamma (IFNy) secretion in vitro, confirming the anti-inflammatory phenotype. Mouse FRβ (mFRβ)-targeting CAR T cells were engineered and infused into ovarian tumor-bearing mice, resulting in depletion of FRβ+ TAMs, a delay in tumor growth (not attributable to the mFRβ-CAR T cells), increased recruitment of inflammatory myeloid and activated CD8+ T cells, and overall increased survival. With mFRβ-CAR T cells administered as a pretreatment prior to tumor-specific CAR T cell administration, all mice experienced tumor regression and increased survival. Lastly, the group confirmed that FRβ-expressing TAMs are present in human ovarian cancer ascites samples and can induce a human FRβ-specific CAR T cell response ex vivo. Taken together, this study presents strong proof-of-concept evidence for strategies that target FRβ-expressing M2 TAMs to improve pro-inflammatory immune cell recruitment and thus the anti-tumor effect of CAR T cell therapy.
Why this matters: This study presents an intriguing strategy to remodel the TME using a preconditioning approach, which could be used to complement a variety of immunotherapies for solid tumors, including CAR T cell therapy.
“Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients” by Kazusa Ishii et al
Hyperinflammatory toxicity resembling hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) has been reported secondary to CAR T cell therapy, and the mechanisms driving the pathology remain poorly understood, in part, due to a paucity of animal models. Kazusa Ishii and colleagues used a syngeneic mouse model of anti-CD19 CAR T cell therapy against pre-B cell acute lymphoblastic leukemia to investigate the role of perforin, a granule-mediated cytoxicity molecule associated with primary HLH (a rare heritable condition), in the secondary HLH/MAS-like toxicity seen in some human patients. In vitro and in vivo assessments of perforin knock-out (Prf1-/-) CAR T cells showed reduced cytotoxic and leukemia-clearing capabilities compared to wild-type (WT) CAR T cells, with increased pro-inflammatory gene expression and cytokine production, notably of the interferon-gamma (IFNy) and IL-1 families. Interestingly, early CAR T cell expansion in vivo was similar between WT and Prf1-/- CAR T cells, but between 8 and 20 days post-engraftment a second expansion of Prf1-/- CAR T cells occurred, resulting in HLH-like phenotypes such as splenomegaly with increased hemophagocytes and
an expansion in recipient-derived immune cells. Notably, neutralization/inhibition of IFNy and IL-1 did not completely rescue the late-onset HLH-like phenotype. Importantly, the phenotypes seen in the murine model closely resembled the biphasic toxicity observed in a subset of patients receiving anti-CD22 CAR T cell therapy, where 38% of patients who experienced cytokine release syndrome (CRS) within the expected window after infusion also experienced HLH-like toxicity thereafter at a median onset of 14 days. This study not only presents a potential perforin-mediated mechanism of HLH/MAS to be further explored for therapeutic targeting to reduce toxicity, but also highlights a mouse model that closely resembles human phenotypes of HLH/MAS-like toxicity, enabling future investigations.
Why this matters: Little mechanistic insight exists to guide clinicians in treating late HLH/MAS-like toxicity after CAR T cell therapy. This study opens the door for future investigations to fill this gap in knowledge and improve patient care.
“Engineered off-the-shelf therapeutic T cells resist host immune rejection” by Feiyan Mo et al
Autologous CAR T cells minimize the risk of graft-versus-host and host-versus-graft effects, but manufacturing efficiency and consistency are major limitations. Feiyan Mo and colleagues developed a strategy to overcome rejection of ‘off-the-shelf’ adoptive cell therapies using an engineered chimeric 4-1BB-specific alloimmune defense receptor (ADR) T cell model. They found that the ADR T cells were specific in targeting activated (4-1BB-expressing) CD8+ and CD4+ T cells, and NK cells in vitro, which allowed them to resist alloimmune rejection. These results were recapitulated in a B cell leukemia mouse model. Coexpression of the ADR on allogeneic CD19-directed CAR T cells (ADR.CAR T cells) allowed for simultaneous targeting of CD19- and 4-1BB-expressing cells in vitro. In mice previously infused with recipient T cells (RTCs), ADR T cells resisted rejection but were unable to eradicate leukemia. However, ADR.CAR T cells expanded and persisted long-term alongside RTCs and successfully eradicated leukemia in 17 of 19 mice. ADR.CAR T cells were also successful in eliminating neuroblastoma in a xenograft mouse model. To test a potential ‘off-the-shelf' T cell product, ADR and an anti-CD19 CAR were transduced on T cell receptor knock out T cells, and the addition of the ADR allowed these cells to persist and expand with successful leukemia clearance. Altogether, this study presents a promising strategy for developing ‘off-the-shelf' allogeneic CAR T cells for treatment of both hematologic and solid tumors, while eliminating graft-versus-host or host-versus-graft effects.
Why this matters: Previous strategies to engineer allogeneic CAR T cells that circumvent alloimmune rejection showed limited success suppressing both recipient T cells and all subtypes of NK cells. This model—using 4-1BB to target the transactivation state of both cell types—overcomes this hurdle, representing a big step forward in the collective goal of clinically-available ‘off-the-shelf’ CAR T cells.
“Outcomes in patients with DLBCL treated with commercial CAR T cells compared with alternate therapies” by David Sermer et al
The 2017 approval of CAR T cell therapy for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) after two prior lines of therapy was based on single-arm, phase II studies that showed
impressive complete response (CR) rates (40% to 60%) but lacked comparator groups. In a retrospective single-center study, David Sermer and colleagues compared outcomes in 215 total patients with DLBCL treated with either a commercial CAR T cell therapy (tisagenlecleucel or axicabtagene ciloleucel) or systemic therapies (most commonly platinum-based regimens, investigational agents, etoposide-based regimens, and anthracycline-based regimens). At a median follow-up of 14.6 months (range 1.2 to 18.9), the CAR T cell-treated group had statistically significant improvements in overall response rate (ORR) (72% versus 32%), CR rate (52% versus 22%), median overall survival (OS) (19.3 versus 6.5 months), and median progression-free survival (PFS) (5.2 versus 2.3 months) compared to systemic therapies. Subgroup analyses, however, revealed important nuances to these data. For patients with 2, 3, and 4 or more lines of prior therapy, CAR T cell treatment continued to lead to improved PFS and ORR. However, when accounting for unfavorable pre-treatment disease states such as lactate dehydrogenase elevation, bulky disease, Eastern Cooperative Oncology Group (ECOG) status, and extranodal disease, there was no difference in PFS and OS between treatment groups (ORR remained improved for CAR T treated patients), likely because patients with aggressive disease may not be able to delay treatment while awaiting CAR T cell manufacturing. Further, of the responding patients, CAR T cell therapy resulted in worse rates of relapse or progression, consistent with other follow-up studies. Overall, this study presents valuable insights into real-world clinical outcomes and underlines the need for further studies on treatment sequencing with CAR T cells and biomarkers for treatment response.
Why this matters: To date, CAR T cell therapy for treatment of DLBCL is associated with impressive initial responses but relapse remains common. Clinicians currently have little data to inform the choice of one therapy over another for patients with heavily treated DLBCL. This study describes real-world outcomes for CAR T cell therapies used in a variety of settings, and thus may aid clinicians in choosing the appropriate therapies for their patients.
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