My view is, with all major breakthroughs in the treatment of patients, medical practitioners need to learn the procedure. This is no Different.
This is from the other Christine Brown Glioblastoma trial at City of Hope. Might not be a bad thing following their lead.
https://www.nature.com/articles/s41591-024-02875-1
"This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process."
Discussion
To our knowledge, we report the largest CAR-T clinical trial in brain tumors, assessing the feasibility, safety and bioactivity of IL-13Rα2-CAR-T cells in rGBM and other HGGs. Three routes of locoregional delivery were evaluated (ICT, ICV and dual ICT/ICV) along with two manufacturing platforms (Tcm versus Tn/mem). Key findings include the following: (1) repetitive locoregional administration of IL-13Rα2-CAR-T cells is feasible and safe with no DLTs; (2) clinical benefit was observed in a subset of patients, including improved QOL, extended SD and transient radiographic response; (3) elevations in inflammatory and immune modulatory cytokines in the CSF and TCF occurred after each infusion, with the IFNγ pathway as a potential biomarker of CAR activity; (4) patients treated on arm 5 (dual ICT/ICV; Tnmem) displayed the greatest IFNγ-pathway induction in the CSF, and statistically significant improvement in OS as compared to other treatment arms; and (5) high pretreatment tumor T cell levels correlated with a significant survival benefit.
CAR-T products with a less-differentiated memory phenotype are positively associated with clinical response in hematological malignancies26,38,39. Products used in this clinical trial were manufactured from less-differentiated memory T cell subsets (Tcm and Tn/mem) with the intent of reducing levels of dysfunctional T cells reported in GBM29, improving potency and decreasing interpatient product heterogeneity. The Tn/mem platform improved manufacturing feasibility, increased product homogeneity, promoted a favorable less-differentiated phenotype (CD62L+, CCR7+ and CD27+), and displayed the highest CAR-T persistence in blood. Arm 5 utilizing Tn/mem-derived CAR-T products, exhibited the best OS compared to other treatment arms, consistent with previous reports of Tn/mem-derived outperforming Tcm-derived CAR-T products and mediating encouraging clinical benefit against hematological tumors22,23,25,27.
We chose to move forward with dual delivery in arms 4 and 5 to incorporate potentially unique attributes for each delivery route, with ICV delivery being advantageous for treating multifocal tumors, and ICT being beneficial for eradicating unifocal tumors16,20,21. However, mechanistic underpinnings for CAR-T trafficking based on delivery routes warrants further investigation. Locoregionally delivered CAR-T cells were detected in the peripheral blood, and CAR-T trafficking between the CSF and blood could be of clinical significance as CAR-T cells would be expected to maintain their effector activity34. Despite the detection of systemic CAR-T cells in the blood, we did not observe systemic toxicities. However, future studies will measure testosterone levels following IL-13Rα2-CAR-T therapy in males to specifically evaluate potential on-target, off-tumor activity, as IL-13Rα2 is a cancer-testis antigen40.
Analysis of cytokine dynamics revealed treatment related upregulation in proinflammatory/immune stimulatory cytokines in the CSF, as reported for other brain tumor studies evaluating CAR-T therapy7,11,12. Of note, IFNγ-pathway-related cytokines/chemokines (IFNγ, CXCL9 and CXCL10) were elevated in the CNS (CSF and TCF), with the highest levels in arm 5 patients. When evaluating clinical outcomes, the IFNγ pathway positively correlated with time to progression and best response. IFNγ-inducible chemokines CXCL9 and CXCL10 are ligands for CXCR3, a receptor expressed by diverse immune populations and reported to play important roles in immune cell recruitment and tumor immunity41. Overall, our findings demonstrate that liquid biopsy of the CNS was instructive for understanding treatment-related effects and suggest that CAR-T-induced IFNγ, CXCL9 and CXCL10 could be a clinically meaningful biomarker for patient response.
While the prognostic and predictive roles of the TME have been described for some solid tumors in the context of immunotherapy42,43, only recently has the importance of pretreatment TME for CAR-T therapy been reported for hematological malignancies35. The relationship between tumor contexture and responsiveness to CAR-T therapy has not been reported in more immunosuppressive solid tumors, such as GBM. Previously we reported that a patient with rGBM who achieved a CR to IL-13Rα2-CAR-T therapy despite heterogenous IL-13Rα2 expression had a T-cell-rich TME and, following CAR-T treatment, showed evidence for activation of host immunity6,13. Leveraging tumor samples from 57 evaluable patients on this trial, we demonstrate that pretreatment tumor CD3+ T cell levels positively correlated with enhanced survival following CAR-T therapy. While some studies have reported that T cell infiltrates positively correlate with survival of patients with GBM44,45,46, the participants treated on this trial had recurred through prior therapies and were actively progressing at the time of CAR-T treatment. Despite this, tumors with high/intermediate T cell infiltrates not only showed improved outcomes to CAR-T therapy, but in some instances, response (that is, PFS) was longer than initial response to SOC at diagnosis. Taken together, our findings suggest that a ‘hot’ TME plays a critical role in response to CAR-T therapy13.
Limitations of our study include the multiple treatment arms and dose schedules for correlative comparisons and the relatively small number of tumors with intermediate/high CD3 infiltrates. Our statistical analyses, however, aimed to account for these limitations. For instance, our logistic modeling allowed us to uncouple product fitness (Tn/mem) and tumor contexture (CD3), two parameters identified in our trial to positively impact CAR-T therapy. Our modeling also confirmed that tumor ‘hotness’ defined by CD3 density is a dominant feature impacting patient survival following CAR-T therapy. Of interest, clinical benefit was independent of manufacturing process, with Tn/mem-derived CAR products showing no benefit over Tcm. By comparison, our modeling suggests that CAR product was an important determinant for OS in ‘cold’ tumors, with Tn/mem outperforming Tcm. Future randomized studies in larger patient cohorts are needed to confirm and build on our findings related to the critical parameters for successful CAR-T therapy.
In summary, primary objectives of this phase I clinical study were met, establishing feasibility and safety of locoregionally delivered IL-13Rα2-CAR-T cells for treatment of rHGG and rGBM. Although we do not intend to proceed with arms 1–4 for future phase trials, these initial arms provided critical insights to the application of CAR-T cells for the treatment of malignant brain tumors, as no other study has compared the feasibility and safety of various CNS delivery routes. Instead, our intention is to move forward with arm 5, which achieved a MFD of 200 × 106 CAR-T cells per infusion and displayed the best OS of 10.2 months. Our post hoc analysis found that arm 5 survived longer than treatment arms 1–4, which provided a reasonable benchmark control group since enrollment criteria remained consistent over trial execution and participants on arms 1–4 had similar baseline patient characteristics as arm 5. However, due to limitations for post hoc analyses and because this was a nonrandomized trial a survival benefit cannot be inferred. While it will be important to confirm our findings in later-phase trials, OS for the heavily pretreated rGBM cohort, the majority of which were treated at second recurrence or later, compared favorably with historical controls. Median OS for GBM at first recurrence ranges from 5.5 to 12.6 months47 and post bevacizumab from 3.3 to 3.4 months48. The phase III trial evaluating tumor treating fields versus chemotherapy, which, as with our study, treated the majority of patients at second recurrence or later and allowed prior bevacizumab, reported a median OS of 6.6 and 6.0 months, respectively49. Current efforts are now aimed at next-generation CAR designs and combination therapies to address known barriers to more effective therapy, and thus enhance response rates and durability of the arm 5 platform.
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