Why This Matters:
This is one of three recent papers exploring glioma treatment with CAR T using either conventional CAR T targeting the IL-13Rα2 alone (“Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial” by Christine E Brown et al) or in combination with targeting of the epidermal growth factor receptor (EGFR) (“Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results” by Stephen J. Bagley et al). Uniquely, the Choi paper targeted the EGFRVIII as well as secreted a so-called T-cell–engaging molecule (TEAM). Transient responses were seen in all three, enabling greater hope for this strategy of intraventricular or direct injection of immunologically active CART cells.
“PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function” by Matteo Morotti et al
Nature (2024)
Abstract:
Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ–IL2Rγc membrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Now that tumor infiltrating lymphocyte (TIL) administration has been approved by the FDA for treatment of patients with melanoma, finding improved means to enhance in vitro expansion and limit their inhibition following transfer in vivo would be important in terms of enhancing their application to this and other tumors. We have known that PGE2, produced largely by tissue and tumor macrophages, was immunosuppressive for dendritic cells. Here, the Coukos laboratory demonstrates the mechanism by which it acts directly on T cells to limit expression of the IL-2R γc chain and thereby less proliferative. This suggests means to enhance expansion and limit their suppression following transfer.
“Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility” by Shravan Leonard-Murali et al
Nat Commun (2024)
Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.
Why this matters:
Although harboring an unusually low tumor mutational burden (TMB), uveal melanoma can now be treated with bispecific antibodies targeting the gp100 melanoma tumor antigen as well as, in some patients, with expanded tumor infiltrating lymphocytes (TIL). Identifying patients with a transcriptional profile of biopsied lesions predicting successful growth of TIL could allow identification of suitable patients for therapy without subjecting them to an operation to resect tumor. Having identified such patients with low TMB suitable for treatment, this creates hope for other checkpoint blockade or IL-2 treatment resistant patients for novel immunotherapies such as TIL.
“Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127” by Skye Montoya et al
Science (2024)
Increasing use of covalent and noncovalent inhibitors of Bruton’s tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.
A new generation of targeted protein degraders (TPD) based on cereblon or other E3 ligases coupling to neosubstrates is increasingly available targeting various molecules such as the estrogen or androgen receptors. Here, Skye Montoya and colleagues have degraded Bruton’s Tyrosine Kinase (BTK), a target for several kinase inhibitors as part of effective lymphoma treatment, as well as Aiolos and Ikaros (IKZF1/3). Many patients lose sensitivity to these drugs because of mutations within the kinase domain but are still susceptible to the TPDs that depend on their scaffold function for activity. This opens a new domain of emergent small molecules that could be used in vivo in patients as oral drugs targeting important immunologic targets or ex vivo in the setting of expanded T cells for therapy as part of novel IO strategies.