Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors

Spear, Paul W.; Barber, Amorette; Sentman, Charles L.

doi:10.4161/onci.23564

Cited by 48 publications

(37 citation statements)

References 40 publications

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“…148 CARs are limited in their ability to target only one antigen, making them more restricted than whole patient-derived TILs, however more recent data suggests that initial CAR T-cell activity may mobilize and activate endogenous CD4C and CD8C TILs to broaden the anti-tumor response in a mouse ovarian cancer model. 149 The cooperation of TILs with CAR T-cells, and the success of CAR T-cells in such preclinical models, shows promise for emerging immunotherapy trials.…”

Section: Additional Directions In Immunotherapymentioning

confidence: 99%

Tumor infiltrating lymphocytes in ovarian cancer

Santoiemma

Powell

2015

Cancer Biology & Therapy

303

229

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The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and geneengineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. IntroductionTumor infiltrating lymphocytes (TILs) are present in ovarian cancer and are prognostic for increased survival. Given the impact of immunomodulatory regimens in melanoma, renal cell carcinoma, and lung cancer, and the recent elucidation of bona fide tumor-reactive TILs in ovarian cancer, the development of approaches that mobilize tumor-reactive TILs for successful eradication of ovarian cancer is now a high priority. In spite of strong rationale, attempts at administration of adoptive T cell transfer, immune enhancing antibody, and tumor immune environment conditioning in ovarian cancer have been minimal with some positive results reported in patients. In light of the recent development of new immunotherapeutic agents and treatment regimens that bolster host TIL activity, we review the current understanding of the immunobiology of human ovarian cancer including the impact of TIL subset accumulation on ovarian cancer survival and the effect of immune activation in the tumor microenvironment, and conclude that a new line of cancer immunotherapy investigations is warranted in ovarian carcinoma.Ovarian cancer is the second most common and most lethal gynecologic malignancy in the United States with approximately 22,000 new cases and 14,000 deaths expected in 2013.1 Ovarian cancer is often diagnosed at an advanced stage, with the large majority of new cases spread past the primary site. Since there are no current recommendations for ovarian cancer screenings, most efforts at combating ovarian cancer have been targeted at the discovery of new treatments rather than preventative measures. Currently, surgical staging and cytoreduction followed by chemotherapy is the mainstay of treatment, although in some cases neo-adjuvant chemotherapy is attempted.2 The standard for surgical staging consists of total hysterectomy and bilateral salpingooophrectomy with pelvic and para-aortic lymph node di...

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Section: Additional Directions In Immunotherapymentioning

confidence: 99%

Tumor infiltrating lymphocytes in ovarian cancer

Santoiemma

Powell

2015

Cancer Biology & Therapy

303

229

View full text Add to dashboard Cite

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“…Another candidate chemokine receptor that may be used to enhance ACT efficacy is CXCR3. An interesting study reported that adoptive transfer of T cells expressing a NKG2D-based CAR could recruit and activate endogenous antigen-specific CD4 þ and CD8 þ T cells at the tumor site in a CXCR3-dependent manner to achieve optimal eradication of ID8 ovarian cancer (54). Potential treatments such as PD-1 blockade (55) and chemotherapy (18) have been shown to enhance recruitment of adoptively transferred T cells to the tumor site by elevating the level of CXCR3 ligands.…”

Section: Adoptive T-cell Transfer and Traffickingmentioning

confidence: 99%

Trafficking of T Cells into Tumors

2014

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T cells are a crucial component of the immune response to infection and cancer. In addition to coordinating immunity in lymphoid tissue, T cells play a vital role at the disease site, which relies on their efficient and specific trafficking capabilities. The process of T-cell trafficking is highly dynamic, involving a series of distinct processes, which include rolling, adhesion, extravasation, and chemotaxis. Trafficking of T cells to the tumor microenvironment is critical for the success of cancer immunotherapies such as adoptive cellular transfer. Although this approach has achieved some remarkable responses in patients with advanced melanoma and hematologic malignancy, the success against solid cancers has been more moderate. One of the major challenges for adoptive immunotherapy is to be able to effectively target a higher frequency of T cells to the tumor microenvironment, overcoming hurdles associated with immunosuppression and aberrant vasculature. This review summarizes recent advances in our understanding of T-cell migration in solid cancer and immunotherapy based on the adoptive transfer of natural or genetically engineered tumor-specific T cells and discusses new strategies that may enhance the trafficking of these cells, leading to effective eradication of solid cancer and metastases. Cancer Res; 74(24); 7168-74. Ó2014 AACR.

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“…Studies of this approach in immune competent models are also planned, in light of the known immunomodulatory effects of carboplatin (42,43). In addition, recent data suggest that CARengineered T cells may enhance endogenous antitumor immunity against EOC, further emphasizing the need for such studies (44).…”

Section: Discussionmentioning

confidence: 99%

Synergistic Chemoimmunotherapy of Epithelial Ovarian Cancer Using ErbB-Retargeted T Cells Combined with Carboplatin

Parente-Pereira

Whilding

Brewig

et al. 2013

The Journal of Immunology

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Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, underscoring the need for better therapies. Adoptive immunotherapy using genetically targeted T cells represents a promising new treatment for hematologic malignancies. However, solid tumors impose additional obstacles, including the lack of suitable targets for safe systemic therapy and the need to achieve effective T cell homing to sites of disease. Because EOC undergoes transcœlomic metastasis, both of these challenges may be circumvented by T cell administration to the peritoneal cavity. In this study, we describe such an immunotherapeutic approach for EOC, in which human T cells were targeted against the extended ErbB family, using a chimeric Ag receptor named T1E28z. T1E28z was coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective ex vivo expansion of engineered T cells using IL-4. Unlike control T cells, T4+ T cells from healthy donors and patients with EOC were activated by and destroyed ErbB+ EOC tumor cell lines and autologous tumor cultures. In vivo antitumor activity was demonstrated in mice bearing established luciferase-expressing SKOV-3 EOC xenografts. Tumor regression was accompanied by mild toxicity, manifested by weight loss. Although efficacy was transient, therapeutic response could be prolonged by repeated T cell administration. Furthermore, prior treatment with noncytotoxic doses of carboplatin sensitized SKOV-3 tumors to T4 immunotherapy, promoting enhanced disease regression using lower doses of T4+ T cells. By combining these approaches, we demonstrate that repeated administration of carboplatin followed by T4+ T cells achieved optimum therapeutic benefit in the absence of significant toxicity, even in mice with advanced tumor burdens.

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Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors

Cited by 48 publications

References 40 publications

Tumor infiltrating lymphocytes in ovarian cancer

Tumor infiltrating lymphocytes in ovarian cancer

Trafficking of T Cells into Tumors

Synergistic Chemoimmunotherapy of Epithelial Ovarian Cancer Using ErbB-Retargeted T Cells Combined with Carboplatin

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