Direct injection of immature dendritic cells into irradiated tumor induces efficient antitumor immunity

Although there are several ways to load tumor antigens to DCs, in vitro preparation of tumor antigens and manipulation of DCs are usually required. Therefore, to develop a simple antitumor immunization method, we examined if direct injection of DCs into tumor apoptosed by ionizing IR could induce efficient antitumor immunity. Ionizing IR with 15 Gy induced apoptosis in tumor maximally after 6 hr. Injection of DCs i.t. into IR tumor induced strong cytotoxicity of splenocytes against tumor cells compared to i.t. injection of DCs or ionizing IR of tumor, both of which induced weak cytotoxicity. In an animal study, i.t. injection of DCs into IR tumor induced therapeutic antitumor immunity against a tumor established at a distant site. Moreover, when TNF-alpha or LPS was added as a danger/maturation signal to DC suspension before i.t. injection, antitumor immunity was significantly potentiated compared to a group treated with i.t. injection of DCs into IR tumor. Our results suggest that injection of DCs into tumor apoptosed by ionizing IR might be a simple and efficient method of immunization against tumor.     

Therapeutic vaccination against murine lymphoma by intratumoral injection of naive dendritic cells

Dendritic cells are potent antigen-presenting cells that can induce both immune responses and tolerance depending on their state of activation. Immunologic tolerance to established tumors is a major impediment for the development of effective cancer immunotherapy. Dendritic cells may be deficient in number or in function at the tumor site. To address this problem, we evaluated the ability of immature na?ve dendritic cells to induce an antitumor immune response when injected directly into a murine B-cell lymphoma. Mice with advanced transplanted syngeneic tumor were given intratumoral injections of bone marrow-derived dendritic cells. Intratumoral dendritic cell injection alone had no antitumor effect. Systemic chemotherapy alone resulted in only transient tumor regression. However, the intratumoral injection of dendritic cells after chemotherapy led to complete, long-term tumor regression in the majority of treated mice. This dendritic cell-mediated antitumor effect was systemic, resulting in simultaneous elimination of the tumor at second uninjected sites. In addition, it resulted in long-term memory with resistance to tumor rechallenge. Both CD4+ and CD8+ T cells are necessary for the antitumor effect. Furthermore, tumors that occasionally recurred in mice with initial complete tumor regression could be retreated by the same combined chemoimmunotherapy approach. These results show that immunotherapy can succeed in the setting of advanced lymphoma if dendritic cells are restored and loaded with tumor antigens in situ at a single tumor site.     

Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells

Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in priming immune responses to tumor. Interleukin (IL)-23 can act directly on DC to promote immunogenic presentation of tumor peptide in vitro. Here, we evaluated the combination of bone marrow-derived DC and IL-23 on the induction of antitumor immunity in a mouse intracranial glioma model. DCs can be transduced by an adenoviral vector coding single-chain mouse IL-23 to express high levels of bioactive IL-23. Intratumoral implantation of IL-23-expressing DCs produced a protective effect on intracranial tumor-bearing mice. The mice consequently gained systemic immunity against the same tumor rechallenge. The protective effect of IL-23-expressing DCs was comparable with or even better than that of IL-12-expressing DCs. IL-23-transduced DC (DC-IL-23) treatment resulted in robust intratumoral CD8(+) and CD4(+) T-cell infiltration and induced a specific TH1-type response to the tumor in regional lymph nodes and spleen at levels greater than those of nontransduced DCs. Moreover, splenocytes from animals treated with DC-IL-23 showed heightened levels of specific CTL activity. In vivo lymphocyte depletion experiments showed that the antitumor immunity induced by DC-IL-23 was mainly dependent on CD8(+) T cells and that CD4(+) T cells and natural killer cells were also involved. In summary, i.t. injection of DC-IL-23 resulted in significant and effective systemic antitumor immunity in intracranial tumor-bearing mice. These findings suggest a new approach to induce potent tumor-specific immunity to intracranial tumors. This approach may have therapeutic potential for treating human glioma.     

Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation.

PURPOSE: We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors. EXPERIMENTAL DESIGN: Intratumoral administration of dendritic cells is one of the individualized immunotherapies; however, the antitumor activity is relatively weak. In this study, we attempted to enhance the antitumor efficacy of the i.t. dendritic cell administration by combining dendritic cells stimulated with Bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) additionally with cryoablative pretreatment of tumors and analyzed the therapeutic mechanisms. RESULTS: These two modifications (cryoablation of tumors and BCG-CWS stimulation of dendritic cells) significantly increases the antitumor effect on both the treated tumor and the untreated tumor, which was distant at the opposite side, in a bilateral s.c. murine CT26 colon cancer model. Further analysis of the augmented antitumor effects revealed that the cryoablative pretreatment enhances the uptake of tumor antigens by the introduced dendritic cells, resulting in the induction of tumor-specific CD8(+) T cells responsible for the in vivo tumor regression of both treated and remote untreated tumors. This novel combination i.t. dendritic cell immunotherapy was effective against well-established large tumors. The antitumor efficacy was further enhanced by depletion of CD4(+)CD25(+)FoxP3(+) regulatory T cells. CONCLUSIONS: This novel dendritic cell immunotherapy with i.t. administration of BCG-CWS-treated dendritic cells following tumor cryoablation could be used for the therapy of cancer patients with multiple metastases.     

Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors

Dendritic cells (DCs) are attractive candidates for innovative cancer immunotherapy by virtue of their potential to function as professional antigen-presenting cells for initiating cellular immune responses. In this study, we evaluated a possible synergy of conventional chemotherapy together with intratumoral injection of syngeneic bone marrow-derived DCs for the treatment of preexisting tumors. Using murine CT26 colon adenocarcinoma cells (parental or modified to express beta-galactosidase as a model tumor antigen) to produce s.c. tumors in syngeneic BALB/c mice, the data demonstrate that direct injections of DCs at the tumor site result in partial eradication of established tumors. Strikingly, the addition of systemic chemotherapy (cyclophosphamide) combined with local intratumoral injection of DCs led to complete tumor regression in the treated animals. The tumor-free mice were able to resist a repeat challenge with the same tumor, suggesting that the animals had acquired long term antitumor immunity. Supporting evidence for the paradigm of systemic chemotherapy and intratumoral administration of DCs was obtained using melanoma B16 syngeneic tumor treated with Adriamycin plus DCs. These novel findings raise the possibility of using this potent strategy of combined intratumoral injections of DCs and systemic chemotherapy for cancer treatment.     

Increased incidence of papillary thyroid microcarcinoma with decreased tumor size of thyroid cancer

The prevalence of papillary thyroid microcarcinoma (PTMC) in thyroid cancer varies from 20.0% to 42.8% with a mean of 30.0%. Most of these patients have benign clinical courses and receive less aggressive therapeutic procedures in most medical centers. This study retrospectively reviewed 30 years data in one institute and compared it with recent publications to illustrate change in trends and influence of PTMC. Incidental PTMC is usually diagnosed as a postoperative microcarcinoma following thyroidectomy for presumably benign thyroid lesions. Subtotal thyroidectomy or lobectomy without radioactive iodide treatment is sufficient to treat incidental PTMC. In contrast, aggressive surgical treatment with ¹³¹I therapy is indicated for non-incidental PTMC. Those with PTMC in the absence of extra-thyroid invasion diagnosed by postoperative permanent section received follow-up if they had initially received subtotal thyroidectomy. In long-term follow-up studies, cancer-specific mortality for PTMC ranged from 0% to 4%. Most of the mortality cases had distant metastasis at the time of surgery. The clinical course and therapeutic strategies for the non-incidental PTMC patients depend on the TNM stage at the time of diagnosis. One-third of PTMC with clinically aggressive behavior cannot be treated as indolent disease. Invasive tumor markers or larger tumor size are useful to predict tumor recurrence or distant metastasis for PTMC.     

Effects of intratumoral injection therapy of dendritic cells combined with hyperthermia for cancer patients

We proceeded with intratumoral injection therapy of dendritic cells (DC) in combination with hyperthermia for 41 cancer patients in the past two years. We confirmed a total of two CR cases (one of them already reported). We report two successful cases in this paper. Case 1: A uterine cervical cancer patient with metastases in cervical and abdominal lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a CR not only in cervical but also in abdominal lymph nodes. Case 2: A sialyl grand cancer patient with metastases in cervical and axillary lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a PR.     

Intratumoral injection of immature dendritic cells (DC) for cancer patients

We proceeded with DC immunotherapy for 21 cancer patients. Immature dendric cells were injected intratumorally to the 16 patients, and three good and effective cases were obtained: case 1: A 69-year-old male patient with papilla-vater carcinoma, case 2: A 49-year-old female patient with gastric cancer, case 3: A 66-year-old male patient with malignant melanoma.     

Anti-tumor effect of intratumoral administration of dendritic cells in combination with TS-1 and OK-432

We investigated the in vivo anti-tumor effect of intratumoral administration of dendritic cells (DCs) after chemotherapy using TS-1, and followed by immunopotentiator OK-432. Both in Meth-A-bearing BALB/c and in SCCV II-bearing C3H/HeN mice, one week of oral administration of TS-1 affected a partial eradication of established tumors. TS-1 followed by DCs and OK-432 resulted in a marked inhibition in tumor growth, and also contributed to a greater prolongation of survival. Cytotoxic activities of tumor-infiltrating lymphocytes and draining lymph node cells against inoculated tumor cells were significantly increased by the therapy. Cytotoxic memory T cells were also induced. The same therapy was also applied to SCCV II-bearing C3H/HeJ mice in which the Toll-like receptor (TLR) 4 is mutated; no immunotherapeutic effect was observed in the mice. These findings suggest that local DC therapy in combination with TS-1 and OK-432 may well be a useful strategy for the treatment of solid tumors, and that TLR4 signaling is involved in the success of this therapy.     

树突状细胞免疫治疗辅助放射治疗抑制小鼠肾癌移植瘤的生长

目的〖HT5"SS〗： 研究树突状细胞免疫治疗联合放射治疗对小鼠肾癌移植瘤的作用。〖HT5W〗方法〖HT5"SS〗： BALB/c小鼠右腋皮下注射 25× 106 Renca肾癌细胞制作移植瘤模型,分为无治疗对照组、单纯放疗组、单纯DC治疗组和DC联合放疗组4组进行治疗。皮下荷瘤的BALB/c小鼠,在第12～16天连续5 d接受肿瘤局部放射治疗,6脉伏电子线,7 Gy/次,并于第11、15、19和22天分别4次在肿瘤部位直接注射未负载肿瘤抗原的DC细胞(1×106/次),第28天处死小鼠。检测各组肿瘤生长速度和瘤体重量,ELISA检测小鼠脾细胞IL2、IFNγ、IL4和IL10分泌水平。〖HT5W〗结果〖HT5"SS〗: 与单纯治疗组比较,DC联合放疗组小鼠的肿瘤生长明显缓慢,体积明显减小,脾细胞分泌的IL2 、IFNγ和IL4的能力显著提高,与其它各组比较均有非常显著性差异(P<001)。〖HT5W〗结论〖HT5"SS〗: 瘤内DC注射免疫治疗联合放疗能够有效地抑制BALB/c小鼠肾癌移植瘤生长,其效果明显好于单一方法治疗。     

吉西他滨化疗联合树突状细胞瘤内注射对小鼠巨大淋巴瘤的治疗作用

目的：观察吉西他滨对荷B细胞淋巴瘤小鼠脾脏中髓源抑制性细胞（myeloid derived suppressor cell, MDSC）的影响,以及吉西他滨化疗联合树突状细胞（dendritic cells, DCs）治疗巨大淋巴瘤的疗效。方法：小鼠皮下接种A20淋巴瘤细胞,30 d后形成巨大肿瘤,流式细胞仪分析吉西他滨化疗前后荷瘤小鼠脾脏中Gr1+CD11b+ MDSC的比例,免疫磁珠纯化的脾脏MDSC体外加入吉西他滨共培养后,AnnexinV/PI标记法检测细胞凋亡;观察荷瘤小鼠接受吉西他滨化疗联合DCs瘤内注射后肿瘤生长情况及小鼠存活期。结果：荷A20淋巴瘤小鼠脾脏中MDSC的比例显著上调,是正常小鼠脾脏中的10倍以上。体外吉西他滨时间依赖性诱导MDSC凋亡与坏死;荷瘤小鼠体内注射吉西他滨后,脾脏中绝大部分的MDSC被清除。单独吉西他滨注射或DCs瘤内注射对肿瘤生长产生一定的抑制作用,小鼠平均存活天数分别为（48.8±3.6）d和（47.2±7.4）d,而对照组小鼠平均存活天数为（38.8±2.2）d;吉西他滨化疗联合DCs瘤内注射后瘤体持续显著缩小,60%小鼠存活时间均超过90 d。结论：吉西他滨可有效清除荷瘤小鼠脾脏MDSC,吉西他滨化疗与DCs瘤内注射免疫治疗具有协同效应,可以提高对巨大淋巴瘤的疗效,本实验为应用生物化疗综合治疗模式治疗复发、难治性淋巴瘤提供了实验依据。     

CY15, a malignant histiocytic tumor that is phenotypically similar to immature dendritic cells

The origin and pathogenesis of histiocytic malignancies and the biology of the tumor cells are poorly understood. We have isolated a murine histiocytic tumor cell line (CY15) from a BALB/c IFNgamma(-/-) mouse and characterized it in terms of phenotype and function. The morphology, as judged by electron microscopy, and the surface marker phenotype suggests that CY15 cells are similar to immature dendritic cells (CD11c (low), MHC II (low), CD11b(+), B7.1(+), B7.2(+), and CD40(+)). The cells form tumors in BALB/c mice and metastasize to spleen, liver, lung, kidney, and to a lesser extend to lymph nodes and bone marrow, as judged by the growth of green fluorescent protein transfected tumor cells in mice. CY15 cells are capable of actively taking up antigen (FITC-ovalbumin) and can stimulate T lymphocytes in an allogenic mixed lymphocyte reaction but less effectively than their normal counterparts (immature dendritic cells). They respond to interleukin 4 (IL-4) with up-regulation of CD11c. If stimulated with IFNgamma the cells up-regulate MHC II, CD40 B7.1, and B7.2. Lipopolysaccharide induces the cells to up-regulate B7.1 and B7.2 and to secrete tumor necrosis factor alpha and IL-12. Based on these data, CY15 is a dendritic cell-like tumor cell line and may serve as a transplantable tumor model for histiocytosis in humans.     

Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin 12.

Bone marrow-derived dendritic cells (BM-DCs) retrovirally transduced with genes encoding murine interleukin (IL)-12 stably expressed bioactive IL-12 protein at high levels. Intratumoral injection with IL-12 gene-modified BM-DCs resulted in regression of day 7 established weakly immunogenic tumors (MCA205, B16, and D122). This antitumor effect was substantially better than that of IL-12-transduced syngeneic fibroblasts or nontransduced BM-DCs. Furthermore, intratumoral injection with IL-12-transduced dendritic cells (DCs) induced specific TH1-type responses to the tumor in regional lymph nodes and spleen at levels greater than those of IL-12-transduced fibroblasts or nontransduced BM-DCs. Trafficking studies confirmed that intratumorally injected IL-12-transduced DCs, but not fibroblasts, could migrate to the draining lymph node to the same extent as nontransduced BM-DCs. This strategy designed to deliver genetically modified DCs to tumor sites is associated with systemic and therapeutic antitumor immunity and is an alternative approach to those that use delivery of DCs loaded with tumor antigen. These results support the clinical application of IL-12 gene-modified DCs in patients with cancer.     

Systemic antitumor effect of intratumoral injection of dendritic cells in combination with local photodynamic therapy.

PURPOSE: Photodynamic therapy (PDT), which is used clinically for the palliative treatment of cancer, induces local tumor cell death but has no effect on tumors in untreated sites. The purpose of this study was to determine if local PDT followed by intratumoral injection of na?ve dendritic cells (IT-DC) induces systemic antitumor immunity that can inhibit the growth of untreated as well as PDT + IT-DC-treated tumors. EXPERIMENTAL DESIGN: BALB/c or C57Bl/6 mice were injected s.c. with CT26 colorectal carcinoma cells and B16 melanoma cells, respectively, and following 10 to 12 days of tumor growth, the tumors were treated with PDT alone or PDT followed by IT-DC or IT-PBS. In other studies, tumors were established simultaneously in both lower flanks or in one flank and in the lungs, but only one flank was treated. RESULTS: Whereas neither PDT nor IT-DC alone was effective, PDT + IT-DC eradicated both CT26 and B16 tumors in a significant proportion of animals and prolonged the survival of mice of which the tumors were not cured. The spleens of mice treated with PDT + IT-DC contained tumor-specific cytotoxic and IFN-gamma-secreting T cells whereas the spleens of control groups did not. Moreover, adoptive transfer of splenocytes from successfully treated CT26 tumor-free mice protected na?ve animals from a subsequent challenge with CT26, and this was mediated mainly by CD8 T cells. Most importantly, PDT plus IT-DC administered to one tumor site led to tumor regression at distant sites, including multiple lung metastases. CONCLUSIONS: PDT + IT-DC induces potent systemic antitumor immunity in mice and should be evaluated in the treatment of human cancer.     

自体不成熟树突状细胞胸腔内注射治疗化疗耐药的肿瘤患者恶性胸腔积液

目的:观察体外扩增的不成熟树突状细胞(dendritic cells,DC)胸腔内注射对恶性胸腔积液的疗效和安全性。方法:从6例对化疗耐药的恶性胸腔积液患者采集外周血单个核细胞,体外细胞因子诱导培养获得不成熟DC,每4周患者胸腔内注射DC(5~10)×107个,连续3次为一疗程,观察治疗后患者胸腔积液的变化及治疗的不良反应,流式细胞仪检测胸水中T细胞、NK细胞亚群。结果:总体疗效为:CR 2例,PR 1例,SD 1例,PD 2例,有效率为50%(3/6),获益率(CR+PR+SD)为66.7%。2例CR均为肾癌患者,缓解时间达26周和147周;3例肺癌患者中1例PR、1例SD及1例PD;1例恶性胸膜间皮瘤PD;治疗中无严重不良反应发生。DC治疗后6例患者胸水中的T细胞百分率均较治疗前上升,但差异无统计学意义;NK细胞百分率较治疗前明显上升(P<0.05)。结论:采用无抗原加载的自体不成熟DC胸腔内注射治疗恶性胸腔积液的疗效肯定,可能主要是通过NK细胞介导,是一种安全、有效的治疗方法。     

Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles

Dendritic cells (DCs) are potent antigen-presenting cells that play a pivotal role in regulating immune responses in cancer and have recently been shown to be activated by heat shock proteins (HSPs). We previously reported that HSP70 expression after hyperthermia induces antitumor immunity. Our hyperthermia system using magnetite cationic liposomes (MCLs) induced necrotic cell death that was correlated with HSP70 release. In the present study, we investigated the therapeutic effects of DC therapy combined with MCL-induced hyperthermia on mouse melanoma. In an in vitro study, when immature DCs were pulsed with mouse B16 melanoma cells heated at 43 degrees C, major histocompatibility complex (MHC) class I/II, costimulatory molecules CD80/CD86 and CCR7 in the DCs were upregulated, thus resulting in DC maturation. C57BL/6 mice bearing a melanoma nodule were subjected to combination therapy using hyperthermia and DC immunotherapy in vivo by means of tumor-specific hyperthermia using MCLs and directly injected immature DCs. Mice were divided into 4 groups: group I (control), group II (hyperthermia), group III (DC therapy) and group IV (hyperthermia + DC therapy). Complete regression of tumors was observed in 60% of mice in group IV, while no tumor regression was seen among mice in the other groups. Increased cytotoxic T lymphocyte (CTL) and natural killer (NK) activity was observed on in vitro cytotoxicity assay using splenocytes in the cured mice treated with combination therapy, and the cured mice rejected a second challenge of B16 melanoma cells. This study has important implications for the application of MCL-induced hyperthermia plus DC therapy in patients with advanced malignancies as a novel cancer therapy.     

Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients

Immunosuppression mediated by regulatory T cells (Tregs) is a key facilitator of tumor immune evasion, but the source of these Tregs and their contribution to human cancer progression remains unclear. This study investigated the properties of FoxP3⁺ Tregs, their prognostic value in patients with hepatocellular carcinoma (HCC) and the underlying mechanisms of FoxP3⁺ Treg intratumoral accumulation. In addition to an increased number of circulating FoxP3⁺ Tregs, the results also showed that FoxP3⁺ Tregs gathered in the tumor site, where they suppressed tissue‐derived CD4⁺CD25^? T‐cell activation (p < 0.001), promoting disease progression and poor prognosis in HCC patients (< 0.01). The intratumoral prevalence of FoxP3⁺ Tregs was associated with a high density of macrophages (Mφ) (p < 0.001). Depletion of tissue Mφ thus attenuated the increase of liver FoxP3⁺ Treg frequency attributed to in vivo inoculation with hepatoma (p = 0.01), whereas Mφ exposed to tumor culture supernatants from hepatoma‐derived cell lines increased FoxP3⁺ Treg frequency in vitro (p < 0.001). This increase was partially blocked by antiinterleukin‐10 antibody (p < 0.01). In conclusion, tumor‐associated Mφ may trigger a rise of the intratumoral FoxP3⁺ Treg population, which in turn may promote HCC progression. © 2009 UICC     

Antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene.

PURPOSE: Dendritic cells (DCs) are attractive effectors for cancer immunotherapy because of their potential to function as professional antigen-presenting cells for initiating cellular immune responses. The tumor suppressor gene p53 is pivotal in the regulation of apoptosis, and approximately 50% of human malignancies exhibit mutation and aberrant expression of p53. We investigated the antitumor effect of intratumoral administration of bone marrow-derived dendritic cells transduced with wild-type p53 gene. EXPERIMENTAL DESIGN: We examined whether intratumoral administration of DCs infected with recombinant adenovirus expressing murine wild-type p53 (Ad-mp53) could induce systemic antitumor responses against mutant p53-expressing tumors, highly immunogenic MethA, or weakly immunogenic MCA-207 implanted in syngeneic mice. RESULTS: Accumulation of wild-type p53 protein in bone marrow-derived murine DCs could be successfully achieved by Ad-mp53 infection. Treatment with intratumoral injection of Ad-mp53-transduced DCs caused a marked reduction in the in vivo growth of established MethA and MCA-207 tumors with massive cellular infiltrates. Administration of p53-expressing DCs suppressed the growth of both injected MCA-207 tumors and untreated distant MCA-207 tumors, but not unrelated Lewis lung carcinoma tumors, suggesting the augmentation of systemic immunogenicity against MCA-207 tumor cells. Moreover, intratumoral injection of p53-expressing DCs had a greater antitumor effect than did s.c. immunization. CONCLUSIONS: Our results indicate that intratumoral administration of DCs expressing murine wild-type p53 leads to significant systemic immune responses and potent antitumor effects in mutant p53-expressing murine cancer models. These findings raise the possibility of using this strategy of intratumoral injection of p53-expressing DCs for human cancer treatment.     

Immunotherapy of solid tumor by intratumoral infusion of lymphokine-activated killer cells

Fifty million lymphokine-activated killer (LAK) cells were infused into rat T9 gliosarcoma tumors for 1 hr at an infusion rate of 0.1 ml/hr. Cultured normal spleen cells were infused into similar tumors as a control. The LAK cell-treated tumors began to regress at approximately 3 weeks after infusion and disappeared by 6 weeks, while the cultured normal spleen cell-treated tumors grew progressively. Immunohistochemical analysis demonstrated prominent infiltration of cytotoxic/suppressor T cells in the LAK cell-treated tumors, while few lymphocytes were recognized in the control tumors. These data suggested that LAK cells infused intratumorally might be capable of mediating tumor regression by inducing host immunity against the tumor.