Oncolytic Adenoviruses Armed with Tumor Necrosis Factor Alpha and Interleukin-2 Enable Successful Adoptive Cell Therapy

Abstract

Adoptive cell therapy holds much promise in the treatment of cancer but results in solid tumors have been modest. The notable exception is tumor-infiltrating lymphocyte (TIL) therapy of melanoma, but this approach only works with high-dose preconditioning chemotherapy and systemic interleukin (IL)-2 postconditioning, both of which are associated with toxicities. To improve and broaden the applicability of adoptive cell transfer, we constructed oncolytic adenoviruses coding for human IL-2 (hIL2), tumor necrosis factor alpha (TNF-α), or both. The viruses showed potent antitumor efficacy against human tumors in immunocompromised severe combined immunodeficiency (SCID) mice. In immunocompetent Syrian hamsters, we combined the viruses with TIL transfer and were able to cure 100% of the animals. Cured animals were protected against tumor re-challenge, indicating a memory response. Arming with IL-2 and TNF-α increased the frequency of both CD4+ and CD8+ TILs in vivo and augmented splenocyte proliferation ex vivo, suggesting that the cytokines were important for T cell persistence and proliferation. Cytokine expression was limited to tumors and treatment-related signs of systemic toxicity were absent, suggesting safety. To conclude, cytokine-armed oncolytic adenoviruses enhanced adoptive cell therapy by favorable alteration of the tumor microenvironment. A clinical trial is in progress to study the utility of Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123) in human patients with cancer.

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

“…This could invigorate TIL activity in the context of ACT, as shown in melanoma and pancreatic cancer. 20 This is further supported by efficacy data from patient cohorts, where patients with OVCA appeared to benefit from oncolytic adenovirus therapy. 21 Importantly, among a panel of FDA-approved cytokines, TNFa and IL-2 was the combination of cytokines that best synergized with antitumor T cells in our preclinical studies.…”

“…21 Importantly, among a panel of FDA-approved cytokines, TNFa and IL-2 was the combination of cytokines that best synergized with antitumor T cells in our preclinical studies. 22 23 This translated into promising safety, efficacy and survival results in animals bearing melanoma and pancreatic tumors, following adoptive transfer of TILs, 20 T-cell receptor-engineered T cells 22 and chimeric antigen receptor T cells. 24 Such outcome is attributed to a decrease in intratumororal immunosuppression and, improved trafficking and activation of transferred T cells.…”

“…27 To generate Ad5/3-E2F-D24-hTNFa-IRES-hIL2, we inserted the cytokine transgenes in the E3 region of Ad5/3-E2F-D24 using bacterial artificial chromosomerecombineering strategy based on the selection marker galK. 20 Both viruses were manufactured using a cesium chloride gradient and the concentration was determined by optical density at 260 nm.…”

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“…The cell death after electrotransfer of pDNA using the EP1 pulse protocol could be a consequence of the production of IFNβ and TNFα. TNFα has shown an antitumor effect on tumor cells or tumors in combination with other treatments [84][85][86][87][88]. Cell lines that possess receptors for INFβ and/ or TNFα and receptor binding can activate necroptosis or apoptosis [89,90].…”

Oncolytic adenovirus: A tool for cancer therapy in combination with other therapeutic approaches

“…, and causes apoptosis and necrosis of cancer cells(Mocellin et al, 2005) Havunen et al (2017). engineered an OAd for expressing human IL-2 and TNF-α (Ad5/3-E2Fd24-hTNFa-IRES-hIL12 or TILT-123).…”