The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Immune Cell Therapies and Immune Cell Engineering co-Section Editor Dr. Aude Chapuis.
“Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors” by Gabriel Espinosa-Carrasco et al
Cancer Cell (2024)
Abstract:
Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4+ T cells and triads are required for CD8+ T cell cytotoxicity during the effector phase and tumor elimination.
Why this matters:
In immune-checkpoint blockade (ICB) or vaccine settings, tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. Modelling this, this group gave mice with solid tumors only cytotoxic T cells and compared to mice that had received both cytotoxic T cells and helper T cells. Tumor regression was only observed in the mice that had received both and in which physical triads, composed of one dendritic cell, one CD8 T cell, and one helper T cell were identified such that the cytotoxic T cells are licensed to kill. Going back to patients with pleural mesothelioma treated with ICB, triads were clearly associated with clinical responses. For adoptive immunotherapy settings or vaccine settings, this underscores the necessity of engaging CD4 T cells responses for tumor regression.
“Engineered CD47 protects T cells for enhanced antitumour immunity” by Sean A Yamada-Hunter et al
Nature (2024)
Abstract:
Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.
Why this matters:
Augmenting tumor-associated macrophages (TAM) phagocytic activity by blocking the CD47-SIRPa axis has shown promise but not definitive efficacy in human solid tumors. Combining blocking of the CD47-SIRPa boosts TAMs to phagocytose and therefore further abrogates the efficacy of aACT in solid tumors. To circumvent this paradox, this group engineered a CD47 variant expressed on T cells which allows SIRPa engagement but not recognition by the anti-CD47 antibodies. In combination with anti-CD47 antibodies, ACT potential was significantly boosted. This suggests clinical strategies to modulate and harness TAMs for increased ACT efficacy in solid tumors are round the corner.
“Naturally occurring T cell mutations enhance engineered T cell therapies by Julie Garcia” et al
Nature (2024)
Abstract:
Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11-PIK3R3, found in a CD4+ cutaneous T cell lymphoma, that augments CARD11-BCL10-MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11-PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.
Why this matters:
This group systematically screened the effects of 71 mutations/alterations identified in T cell neoplasms on T cell signaling, cytokine production and in vivo persistence in solid tumor models. This led to the identification of one gene fusion, CARD11-PIK3R3, identified from a CD4+ cutaneous T cell lymphoma, that increased the proliferation and cytotoxicity of anti-tumor T cells in different CAR and TCR models in an antigen-dependent manner. Although concerns regarding the malignant potential of this approach are justifiable, transferred cells bearing this particular fusion could not persist in the absence of antigen and did not transform after more than 1 year in vivo. Overall, this approach opens the way to individually exploit tumor-specific naturally occurring mutations for clinical benefit.
“TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation” by Vanessa Mühlgrabner et al
Sci Adv. (2024)
Abstract:
Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)-modified T cells and call for alternative antigen receptor designs for effective T cell-based cancer immunotherapy. Here, we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousandfold. TCC-based antigen recognition occurred without adverse nonspecific signaling, which is typically observed in CAR-T cells, and did not depend-unlike sensitized peptide/MHC detection by conventional T cells-on CD4 or CD8 coreceptor engagement. TCC-endowed signaling properties may prove critical when targeting antigens in low abundance and aiming for a durable anticancer response.
Why this matters:
CAR constructs, despite the high affinity of the antibody binders they carry, require high antigen density for recognition and triggering, whereas naturally evolved TCRs, which bind comparatively loosely to peptide/MHC, recognize and trigger with very low antigen densities. Using advanced live cell imaging technology, this group systematically assessed the conveyed antigen sensitivities and downstream signaling of CAR/TCR-based synthetic constructs (TruCs, STAR) to show that these convey superior membrane-proximal signal transmission. These properties may prove critical for low-antigen densities but may also increase on-target off tumor toxicities.
“Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial” by Mark Yarchoan et al
Nat Med. (2024)
Abstract:
Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4+ and CD8+ effector T cells. T cell receptor β-chain (TCRβ) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV's mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 .
Why this matters:
This is one of 4 manuscripts published in Nature Medicine between August 2022 and April 2024 exploring neo-antigen and public mutation-specific vaccines with different platforms. All report responses with circulating tumor DNA instead of RECIST, which is new. In this particular manuscript, the team reports the results of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens co-administered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced previously treated HCC. Responses were quite impressive with an objective response rate of 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. The authors showed increased vaccine-specific T cell responses in blood and tumor. Overall, this is excellent news for the vaccine field, suggesting creative new platforms can lead to better efficacy.