Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA

Chandran, Smita S.; Ma, Jiaqi; Klatt, Martin G.; Dündar, Friederike; Bandlamudi, Chaitanya; Razavi, Pedram; Wen, Hannah Y.; Weigelt, Britta; Zumbo, Paul; Fu, Si Ning; Banks, Lauren B.; Yi, Fei; Vercher, Enric; Etxeberría, Iñaki; Bestman, Watchain D.; Paula, Arnaud Da Cruz; Aricescu, Ilinca S.; Drilon, Alexander; Betel, Doron; Scheinberg, David A.; Baker, Brian M.; Klebanoff, Christopher A.

doi:10.1038/s41591-022-01786-3

Cited by 66 publications

(67 citation statements)

References 76 publications

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“…Novel chemical strategies that do not rely exclusively on ATP competition also appear promising ( 16 – 19 ). Mutant-specific immunotherapy is now also on the horizon ( 20 ).…”

mentioning

confidence: 99%

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

Hart

Liu

Pan

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Nanobodies and chemical cross-linking were used to gain information on the identity and positions of flexible domains of PI3Kα. The application of chemical cross-linking mass spectrometry (CXMS) facilitated the identification of the p85 domains BH, cSH2, and SH3 as well as their docking positions on the PI3Kα catalytic core. Binding of individual nanobodies to PI3Kα induced activation or inhibition of enzyme activity and caused conformational changes that could be correlated with enzyme function. Binding of nanobody Nb3-126 to the BH domain of p85α substantially improved resolution for parts of the PI3Kα complex, and binding of nanobody Nb3-159 induced a conformation of PI3Kα that is distinct from known PI3Kα structures. The analysis of CXMS data also provided mechanistic insights into the molecular underpinning of the flexibility of PI3Kα.

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“…Novel chemical strategies that do not rely exclusively on ATP competition also appear promising ( 16 – 19 ). Mutant-specific immunotherapy is now also on the horizon ( 20 ).…”

mentioning

confidence: 99%

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

Hart

Liu

Pan

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…By tracking the driver mutations shared between several patients, such as in PIK3CA, the first examples of public neoantigens and cognate TCRs have been identified. They carry implications for less personalized, off-the-shelf neoantigen-targeted ACT treatment possibilities in the future [ 177 ]. However, to date, the search for public neoantigens has been rather unsuccessful.…”

Section: Challenges For T Cells In the Tumor Microenvironmentmentioning

confidence: 99%

Paving the Way to Solid Tumors: Challenges and Strategies for Adoptively Transferred Transgenic T Cells in the Tumor Microenvironment

Füchsl

Krackhardt

2022

Cancers

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T cells are important players in the antitumor immune response. Over the past few years, the adoptive transfer of genetically modified, autologous T cells—specifically redirected toward the tumor by expressing either a T cell receptor (TCR) or a chimeric antigen receptor (CAR)—has been adopted for use in the clinic. At the moment, the therapeutic application of CD19- and, increasingly, BCMA-targeting-engineered CAR-T cells have been approved and have yielded partly impressive results in hematologic malignancies. However, employing transgenic T cells for the treatment of solid tumors remains more troublesome, and numerous hurdles within the highly immunosuppressive tumor microenvironment (TME) need to be overcome to achieve tumor control. In this review, we focused on the challenges that these therapies must face on three different levels: infiltrating the tumor, exerting efficient antitumor activity, and overcoming T cell exhaustion and dysfunction. We aimed to discuss different options to pave the way for potent transgenic T cell-mediated tumor rejection by engineering either the TME or the transgenic T cell itself, which responds to the environment.

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“…Public neoantigens, including the newly described PIK3CA public neoantigen [ 6 ], therefore represent an innovative new translational platform to help develop TCR immunotherapies for patients [ 7 ] (see Fig. 1 ).…”

Section: Lessons Learned From Cell Therapiesmentioning

confidence: 99%

Perspectives in Immunotherapy: meeting report from the Immunotherapy Bridge, December 1st–2nd, 2021

et al. 2022

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Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies.The virtual Immunotherapy Bridge (December 1st–2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.

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Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA

Cited by 66 publications

References 76 publications

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

Nanobodies and chemical cross-links advance the structural and functional analysis of PI3Kα

Paving the Way to Solid Tumors: Challenges and Strategies for Adoptively Transferred Transgenic T Cells in the Tumor Microenvironment

Perspectives in Immunotherapy: meeting report from the Immunotherapy Bridge, December 1st–2nd, 2021

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