Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy

Renauer

et al. 2023

Immunological Reviews

SummaryCRISPR technology has transformed multiple fields, including cancer and immunology. CRISPR‐based gene editing and screening empowers direct genomic manipulation of immune cells, opening doors to unbiased functional genetic screens. These screens aid in the discovery of novel factors that regulate and reprogram immune responses, offering novel drug targets. The engineering of immune cells using CRISPR has sparked a transformation in the cellular immunotherapy field, resulting in a multitude of ongoing clinical trials. In this review, we discuss the development and applications of CRISPR and related gene editing technologies in immune cells, focusing on functional genomics screening, gene editing‐based cell therapies, as well as future directions in this rapidly advancing field.

Section: Translation Into the Clinicmentioning

confidence: 99%

Applications of CRISPR technology in cellular immunotherapy

Renauer

et al. 2023

Immunological Reviews

“…A variety of TCRs have been tested by ACT, clinically and/or preclinically, including ones targeting tumor associated antigens (TAA) like the cancer testis antigen NY-ESO-1, 140 melanoma antigen recognized by T cells 1 (MART1) and glycoprotein 100 (gp100), 141 MAGE-A3, 142 MAGE-A4, 143 carbonic anhydrase IX (CAIX), 144 and carcinoembryonic antigen (CEA). 145 In addition, TCRs have been evaluated against human virus-derived targets such as human papilloma virus (HPV)-16 E7, 146,147 neoantigens 148,149 (i.e., peptides generated by non-synonymous mutations in tumor cells that are presented by HLA and recognized by anti-tumor T cells [150][151][152] ), mutant KRAS, 153 public neoantigens, 154 and monomorphic MHC class I related protein (MR1) in an HLA-independent manner. 68 Notably, tumor-specific TCRs, although typically much weaker in affinity and expressed at lower density than CARs, 155 can be triggered to induce full T-cell activation in response to fewer than 100 peptide-HLA complexes.…”

Section: Tcr T-cell Ther Apymentioning

confidence: 99%

Coengineering specificity, safety, and function into T cells for cancer immunotherapy

Giordano Attianese,

Ash,

Irving

2023

Immunological Reviews

SummaryAdoptive T‐cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene‐modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer‐types. The field of ACT has been driven forward by the clinical success of CD19‐CAR therapy against various advanced B‐cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non‐hematological solid tumors. Indeed, in addition to pre‐infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post‐transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T‐cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down‐regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity‐optimized TCRs can improve T‐cell function and innovative CAR designs as well as gene‐modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T‐cell coengineering strategies, including of tools, receptors, and gene‐cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.

“…6 The activation of immune response relies on the production of neoantigen, antigen-presenting, and neoantigen recognized by T cells. [7][8][9] Previous studies have confirmed that neoantigens are one of the important factors in immune response and immunotherapy. 7,10,11 Hypothesis in the immunotherapy field holds the opinion that tumors with increased tumor mutation present more neoantigens and are more immunogenic.…”

Section: Introductionmentioning

confidence: 98%

“…The essence of immunotherapy is the specific recognition and killing effect of effector T cells on tumor cells 6 . The activation of immune response relies on the production of neoantigen, antigen‐presenting, and neoantigen recognized by T cells 7–9 . Previous studies have confirmed that neoantigens are one of the important factors in immune response and immunotherapy 7,10,11 .…”

Section: Introductionmentioning

confidence: 99%

The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity

Wang,

Xu,

Lan

et al. 2023

Cancer Medicine

ObjectivesIntratumor heterogeneity (ITH) is an important factor for clinical outcomes in patients with multiple myeloma (MM). High ITH has been proven to be a key reason for tumor immune escape and treatment resistance. Neoantigens are thought to be associated with ITH, but the specific correlation and functional basis for this remains unclear.MethodsWe study this question through the whole‐exome sequencing (WES) data from 43 high ITH newly diagnosed MM patients in our center. Mutant allele tumor heterogeneity (MATH) was conducted to quantify ITH. The cutoff value for high intratumor heterogeneity was determined by comparing MATH of different kinds of tumors. NeoPredPipe was performed to predict neoantigens and binding affinity.ResultsCompared to other tumors, MM has a relatively low tumor mutation burden but a high ITH. Patients with high MATH had significantly shorter progression‐free survival times than those with low MATH (p = 0.001). In high ITH samples, there is a decrease in strong‐binding neoantigens (p = 0.019). The loss of strong‐binding neoantigens is a key factor for insensitivity to therapy (p = 0.015). Loss of heterozygosity in HLA was not observed. In addition, patients with fewer neoantigens loss had higher rates of disease remission (p = 0.047). CD8 + T cells (p = 0.012) and NK cells (p = 0.011) decreased significantly in patients with high neoantigens loss rate. A prediction model based on neoantigens was built to evaluate the strength of immune escape.ConclusionThe loss of strong‐binding neoantigens explains why tumors with high ITH have a higher degree of immune escape and may be feasible for deciding the clinical treatment of MM.