Intratumoral immunotherapy: using the tumor as the remedy

Marabelle, Aurélien; Tselikas, Lambros; Baère, Thierry De; Houot, Roch

doi:10.1093/annonc/mdx683

Cited by 285 publications

(283 citation statements)

References 59 publications

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“…Direct injection of various biological and chemical agents into tumors as an approach for cancer therapy has a longstanding history with William B. Coley’s efforts in the late 19 th century (Aznar et al, 2017; Marabelle et al, 2017). These agents include but are not limited to TLRs, RIG-I-like receptor (RLR) agonists, STING pathway modulators (Corrales et al, 2016; Li et al, 2017), and oncolytic viruses (Lawler et al, 2017).…”

Section: The Principles To Combine Other Therapeutics With Anti-pd Thmentioning

confidence: 99%

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Sanmamed

Chen

2018

Cell

1,078

557

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Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This “immune enhancement” strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs. This more beneficial tumor response-to-toxicity profile stems from distinct mechanisms of action that restore tumor-induced immune deficiency selectively in the tumor microenvironment, here termed “immune normalization,” which has led to its FDA approval in more than 10 cancer indications and facilitated its combination with different therapies. In this article, we wish to highlight the principles of immune normalization and learn from it, with the ultimate goal to guide better designs for future cancer immunotherapies.

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Section: The Principles To Combine Other Therapeutics With Anti-pd Thmentioning

confidence: 99%

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Sanmamed

Chen

2018

Cell

1,078

557

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“…Intratumoral immunotherapy offers enhanced locoregional efficacy and reduced systemic toxicity by enabling high bioavailability of the agent at the injected tumor sites while limiting systemic exposure . Using tumor as a source of antigens expressed across multiple tumor clones, intratumoral immunotherapies aim to initiate local recruitment of immune cells into the tumor microenvironment and subsequently prime T cells for a systemic polyclonal antitumor response, potentially addressing intra‐ and intertumoral heterogeneity . Several intratumoral therapies with differing mechanisms of action have successfully entered clinical trials and shown promising results (Table ).…”

Section: Intratumoral Immunotherapiesmentioning

confidence: 99%

Intratumoral Immunotherapy—Update 2019

2019

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Intratumoral immunotherapies aim to trigger local and systemic immunologic responses via direct injection of immunostimulatory agents with the goal of tumor cell lysis, followed by release of tumor‐derived antigens and subsequent activation of tumor‐specific effector T cells. In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV‐10 and toll‐like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa‐Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types. Talimogene laherparepvec (T‐VEC), a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy, is the first oncolytic virus approved by the U.S. Food and Drug Administration for the treatment of unresectable melanoma recurrent after initial surgery. In patients with unresectable metastatic melanoma, T‐VEC demonstrated a superior durable response rate (continuous complete response or partial response lasting ≥6 months) over subcutaneous GM‐CSF (16.3% vs. 2.1%; p < .001). Responses were seen in both injected and uninjected lesions including visceral lesions, suggesting a systemic antitumor response. When combined with immune checkpoint inhibitors, T‐VEC significantly improved response rates compared with single agent; similar results were seen with combinations of checkpoint inhibitors and other intratumoral therapies such as CAVATAK, HF10, and TLR9 agonists. In this review, we highlight recent results from clinical trials of key intratumoral immunotherapies that are being evaluated in the clinic, with a focus on T‐VEC in the treatment of advanced melanoma as a model for future solid tumor indications. Implications for Practice This review provides oncologists with the latest information on the development of key intratumoral immunotherapies, particularly oncolytic viruses. Currently, T‐VEC is the only U.S. Food and Drug Administration (FDA)‐approved oncolytic immunotherapy. This article highlights the efficacy and safety data from clinical trials of T‐VEC both as monotherapy and in combination with immune checkpoint inhibitors. This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T‐VEC, the only U.S. FDA‐approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T‐VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

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“…With this in mind, IT injection may enhance tumor-specific T cell responses while reducing significant systemic exposure to healthy tissue and off-target toxicities 43,44 . In addition, IT immunotherapy usually causes in situ priming of antitumor immunity, which may allow a patient's own tumor cells to be used as a therapeutic vaccine 43,44 . In our study, a lower dose of IT anti-PD-1 showed similar therapeutic effects as systemic delivery of a higher dose, and IT anti-CTLA-4 led to complete regression of most 4MOSC1 tumors that are primarily refractory to anti-PD-1.…”

Section: Discussionmentioning

confidence: 99%

Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4

Wang

Allevato

Gilardi

et al. 2019

Preprint

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobaccoassociated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we found that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC.

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Intratumoral immunotherapy: using the tumor as the remedy

Cited by 285 publications

References 59 publications

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Intratumoral Immunotherapy—Update 2019

Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4

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