Combining radiotherapy with immunotherapy: the past, the present and the future

Limbergen, Evert J. Van; Ruysscher, Dirk K. De; Pimentel, Verónica Olivo; Marcus, Damiënne; Berbée, Maaike; Hoeben, Ann; Rekers, Nicolle H.; Theys, Jan; Yaromina, Ala; Dubois, Ludwig

doi:10.1259/bjr.20170157

Cited by 88 publications

(79 citation statements)

References 93 publications

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“…Previous work in various cancer types has identified several mechanisms by which radiotherapy can work synergistically with the immune system and immune-based therapy to target cancer cells. Proposed mechanisms include the induction of new antigens for T cell generation, recruitment of T cells to the region of the tumor, and increasing vulnerability of tumor cells to T cell killing 34. Clinical trials investigating the role of combination radiotherapy and immunotherapy in granulosa cell tumors may therefore be of interest.…”

Section: Discussionmentioning

confidence: 99%

Emerging biomarkers in ovarian granulosa cell tumors

Mills

Chinn

Rauh

et al. 2019

Int J Gynecol Cancer

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ObjectiveAlthough the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches.MethodsImmunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence.Results59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation.ConclusionsBiomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.

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Section: Discussionmentioning

confidence: 99%

Emerging biomarkers in ovarian granulosa cell tumors

Mills

Chinn

Rauh

et al. 2019

Int J Gynecol Cancer

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“…Furthermore, radiotherapy induces antigen presentation and cytokine release of the tumor, which further leads to T-cell recruitment. On the other hand, radiation can induce increased PD-L1 expression in the tumor, hindering the efficiency of attracted T-cells [20]. Currently various clinical phase II and phase III trials explore the combination of radiation therapy and PD-1 inhibition in different tumor entities [18].…”

Section: Introductionmentioning

confidence: 99%

Radiation therapy before radical cystectomy combined with immunotherapy in locally advanced bladder cancer – study protocol of a prospective, single arm, multicenter phase II trial (RACE IT)

et al. 2020

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Background: Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer. Methods: Study design: "RACE IT" (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11-15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune-or radiation therapy.

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“…5,6 In the last decade, cancer immunotherapy has emerged as a clinically effective tool in several solid tumors, particularly in combination with more conventional therapies. 7 There are a variety of approaches in tumor immunotherapy, including manipulation of the immune system through the use of immune agents, such as vaccines, 8 cytokines, 9 checkpoint inhibitors (including anti-programmed death 1 [PD-1]/PD-ligand 1 [PD-L1] antibodies and anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4 antibodies 10,11 ), kinase inhibitors (such as apatinib and gefitinib), 12,13 and immune cells. [14][15][16][17][18][19][20] Among all the possible strategies, cellular immunotherapy has flourished and is widely used in tumor treatment, especially in Asia.…”

Section: Introductionmentioning

confidence: 99%

Rapid expansion in the WAVE bioreactor of clinical scale cells for tumor immunotherapy

Meng

Sun

et al. 2018

Human Vaccines & Immunotherapeutics

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Cell-based immunotherapy using natural killer (NK) cells, cytokine-induced killer (CIK) cells and dendritic cells (DCs) is emerging as a potential novel approach in the auxiliary treatment of a tumor. However, non-standard operation procedure, small-scale cell number, or human error may limit the clinical development of cell-based immunotherapy. To simplify clinical scale NK cells, CIK cells and DCs expansions, we investigated the use of the WAVE bioreactor, a closed system bioreactor that utilizes active perfusion to generate high cell numbers in minimal volumes. We developed an optimized rapid expansion protocol for the WAVE bioreactor that produces clinically relevant number of cells for our adoptive cell transfer clinical protocols. The high proliferative rate, surface phenotypes, and cytotoxicity of these immune cells, as well as the safety of cultivation were analyzed to illuminate the effect of WAVE bioreactor. The results demonstrated that the benefit of utilizing modern WAVE bioreactors in cancer immunotherapy was simple, safe, and flexible production.

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Combining radiotherapy with immunotherapy: the past, the present and the future

Cited by 88 publications

References 93 publications

Emerging biomarkers in ovarian granulosa cell tumors

Emerging biomarkers in ovarian granulosa cell tumors

Radiation therapy before radical cystectomy combined with immunotherapy in locally advanced bladder cancer – study protocol of a prospective, single arm, multicenter phase II trial (RACE IT)

Rapid expansion in the WAVE bioreactor of clinical scale cells for tumor immunotherapy

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