TY - JOUR

T1 - Combination of Oncolytic Virotherapy and CAR T/NK Cell Therapy for the Treatment of Cancer

AU - Kochneva, G.

AU - Sivolobova, G. F.

AU - Tkacheva, A.

AU - Gorchakov, A. A.

AU - Kulemzin, S.

PY - 2020/1

Y1 - 2020/1

N2 - Multiple lines of evidence indicate that CAR-T cell based therapy and oncolytic virotherapy display robust performance in both immunocompetent and immunodeficient mouse models. Rare, yet highly successful attempts to combine these therapeutic platforms have also been reported. Interestingly, both approaches have shown pronounced efficacy in human trials, albeit these were limited to just a handful of malignancies. Specifically, CD19-specific CAR-T cell products (Kymriah and Yescarta) have been highly effective against B cell lymphomas and leukemias, whereas administering oncolytic viruses resulted in pronounced responses in melanoma (Imlygic and Rigvir) and nasopharyngeal carcinoma (Oncorine) patients. It is well established that efficacy of virotherapy as a standalone approach is largely restricted by the pre-existing and mounting immune response against viral antigens, and requires a relatively functional immune system, which is not typical for cancer patients, with the current antitumor therapy schemes. On the other hand, the most important challenges faced by the current CAR-T cell therapy formats include the lack of targetable tumor-specific surface antigens, tumor cell heterogeneity, and immunosuppressive tumor microenvironment, not to mention the unacceptably high costs. Remarkably, combining the two approaches may help address their individual bottlenecks. Namely, local acute inflammatory reaction induced by the viral infection may reverse tumor-associated immunosuppression and lead to more efficient homing and penetration of CAR-expressing lymphocytes into the tumor stroma; combined viral and CAR-mediated cytotoxicity may ensure the production of immunogenic cell debris and efficient presentation of tumor neoantigens, and potently recruit the patient's own bystander immune cells to attack cancer cells. Thus, testing the combinations of CAR-based and virolytic approaches in the clinical setting appears both logical and highly promising.

AB - Multiple lines of evidence indicate that CAR-T cell based therapy and oncolytic virotherapy display robust performance in both immunocompetent and immunodeficient mouse models. Rare, yet highly successful attempts to combine these therapeutic platforms have also been reported. Interestingly, both approaches have shown pronounced efficacy in human trials, albeit these were limited to just a handful of malignancies. Specifically, CD19-specific CAR-T cell products (Kymriah and Yescarta) have been highly effective against B cell lymphomas and leukemias, whereas administering oncolytic viruses resulted in pronounced responses in melanoma (Imlygic and Rigvir) and nasopharyngeal carcinoma (Oncorine) patients. It is well established that efficacy of virotherapy as a standalone approach is largely restricted by the pre-existing and mounting immune response against viral antigens, and requires a relatively functional immune system, which is not typical for cancer patients, with the current antitumor therapy schemes. On the other hand, the most important challenges faced by the current CAR-T cell therapy formats include the lack of targetable tumor-specific surface antigens, tumor cell heterogeneity, and immunosuppressive tumor microenvironment, not to mention the unacceptably high costs. Remarkably, combining the two approaches may help address their individual bottlenecks. Namely, local acute inflammatory reaction induced by the viral infection may reverse tumor-associated immunosuppression and lead to more efficient homing and penetration of CAR-expressing lymphocytes into the tumor stroma; combined viral and CAR-mediated cytotoxicity may ensure the production of immunogenic cell debris and efficient presentation of tumor neoantigens, and potently recruit the patient's own bystander immune cells to attack cancer cells. Thus, testing the combinations of CAR-based and virolytic approaches in the clinical setting appears both logical and highly promising.

KW - oncolytic viruses

KW - chimeric antigen receptors

KW - T-cells

KW - NK-cells

KW - virotherapy

KW - anticancer immunity

KW - cancer therapy

KW - CHIMERIC ANTIGEN RECEPTOR

KW - NATURAL-KILLER-CELL

KW - MODIFIED T-CELLS

KW - ANTITUMOR-ACTIVITY

KW - VACCINIA VIRUS

KW - NK CELLS

KW - CHECKPOINT BLOCKADE

KW - IMMUNOTHERAPY

KW - RESPONSES

KW - DELIVERY

KW - Animals

KW - Humans

KW - Immunotherapy, Adoptive

KW - Killer Cells, Natural/immunology

KW - Neoplasms/immunology

KW - Oncolytic Virotherapy

KW - Oncolytic Viruses/pathogenicity

KW - Receptors, Chimeric Antigen/immunology

KW - Tumor Microenvironment/immunology

U2 - 10.1134/S0026893320010100

DO - 10.1134/S0026893320010100

M3 - Review article

C2 - 32163385

VL - 54

SP - 1

EP - 12

JO - Molecular Biology

JF - Molecular Biology

SN - 0026-8933

IS - 1

ER -