Pathogen boosted adoptive cell transfer immunotherapy to treat solid tumors

Abstract

Because of insufficient migration and antitumor function of transferred T cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive cell transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T cells in vitro with a second T-cell receptor (TCR) that recognizes a bacterial antigen. We then transferred these dual-specific T cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T cells with an increased number and killing ability to the tumors.doptive cell transfer (ACT) of genetically engineered T cells has become a promising cancer immunotherapy for hematologic malignancies (1-4). However, the efficacy of such an approach is curtailed when treating solid tumors (2, 5, 6). The primary hurdles that must be overcome for ACT to be effective against solid tumors include inadequate responses of adoptively transferred T cells, especially in dealing with heterogeneous cancerous cells that bear a wide range of tumor-associated antigens (TAAs) (2, 6); reduced migration of adoptively transferred T cells into the tumor (7); and the immunosuppressive microenvironment within tumors that often induces a rapid loss of T-cell effector function (8).Using infectious pathogens that stimulate a patient's immune system and break immunosuppression in the tumor microenvironment is a century-old strategy that is now being rejuvenated to enhance cancer immunotherapy (9). Bacillus Calmette-Guérin (bacillus Calmette-Guérin), a live attenuated strain of Mycobacterium bovis, has been widely used in treating bladder cancer and melanoma for decades (10, 11). Although effective, bacillus CalmetteGuérin only induces transient and nonspecific antitumor immune responses. To generate a tumor-specific T-cell response, recombinant Listeria monocytogenes (LM) expressing TAAs has recently been developed and shown promising results in treating multiple cancers including breast and pancreatic cancer (9). Owing to the heterogeneity of tumor cells, it remains challenging for recombinant LM-based immunotherapies targeting a single TAA to provide durable and complete regression of cancer because cancer cells that do not express the targeted TAA are able to evade immunosurveillance (2,6,7,9). Thus, there is a critical need for new strategies that generate robust T-cell responses with broad coverage of tumor antigens to improve pathogen-based cancer vaccines.To overcome these hurdles and induce a vigorous antitumor T-cell response, we sought to combine the strength of ACT and pathogen-based can...

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

“…Further, we showed that antitumor CD8 + T cells are shunted from the tumor site (skin) to the distant infection site (lung), resulting in decreased immunity within the tumor, thus permitting accelerated tumor growth (22). Based on these findings and inspired by the previous work of others demonstrating improved anticancer out-comes by targeting pathogens to tumors (23)(24)(25)(26)(27), we hypothesized that infection in the same tissue as the tumor (even if the pathogen were not infecting tumor cells directly) would shunt immune cells to this "shared" site of infection and tumor, and thus inflame the tumor microenvironment to reduce tumor growth and prolong host survival. To test our hypothesis, we utilized the same tumor and infection models as our previous report (22), but here, challenged C57BL/6J (B6) mice with B16-F10 melanoma via i.v.…”

Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

“…Other similar trials are scheduled to start in 2017 in the United States. Prior vaccination with a cancer vaccine can also be used, in an attempt to "prime" rare tumor-specific T-cells [52] . Although ACT has produced remarkable results in clinical trials with melanoma and hematologic malignancies as well as with solid cancers, some deaths have occurred in the trial phases secondary to marked cytokine release ("cytokine storm", or "cytokine release syndrome") and cerebral edema [53] .…”

Two is Better Than One: Advances in Pathogen-Boosted Immunotherapy and Adoptive T-Cell Therapy

“…Our therapy, named re-energized ACT facilitates T-cell penetration and expansion inside the tumor, while reversing the immunosuppressive TME ( Figure 2). As expected, reenergized ACT provoked a strong antitumor immune reaction that led to tumor eradication in around 60% of treated mice and also mediated long-term protection [91]. Independently, another group also utilized combinatorial therapy between ACT and viral vaccination for eradication of large orthotopic solid tumors including breast cancer, sarcoma and colon carcinoma [92].…”

“…Regardless of all these advancements, ACT still fails to produce adequate clinical responses for solid tumors, which requires a robust T-cell-mediated antitumor response. To overcome several limitations simultaneously, we explored the synergistic effect of combining ACT with pathogen-boosted immunotherapy to heighten specificity and efficacy [91]. To achieve this goal, we produced dual-specific T cells that are capable of responding to both tumor and bacterial antigens, and ACT of these cells was performed while administering intratumoral bacteria vaccination.…”