Intracavitary Bacillus Calmette-Guerin in the Treatment of Superficial Bladder Tumors

癌症疫苗能够刺激机体产生特异性免疫性应答，尤其是针对肿瘤抗原的特异性CD8＋的细胞毒T细胞。1994年到1995年间生产的最早的癌症疫苗主要应用于非突变抗原患者中，结果显示肿瘤相关抗原具有一定的免疫原性，而且能够诱导少数晚期癌症患者产生临床反应。过去10年来，技术的发展使我们能够研发针对癌症患者特异性突变抗原的疫苗。多种癌症疫苗正在研发中，包括多肽、蛋白质、抗原提呈细胞(APCs)、肿瘤细胞和病毒载体疫苗。目前肿瘤的标准治疗包括外科、消融、化疗、放疗，都能诱导机体产生抗肿瘤免疫，因此我们认为这些治疗也具有一定的癌症疫苗的效应。通过监测肿瘤患者接受标准治疗前后免疫应答能力的变化，我们找到了肿瘤免疫的生物标志物。正在进行临床试验的联合治疗方案有望成为改善患者预后的最佳策略。

Cancer vaccines

Malignant Melanoma: A Clinicopathological Analysis of the Criteria for Diagnosis and Prognosis

Toll-like receptors (TLRs) have first been characterized for their capacity to detect conserved microbial components like lipopolysaccharide (LPS) and double-stranded RNA, resulting in the elicitation of potent (innate) immune responses against invading pathogens. More recently, TLRs have also been shown to promote the activation of the cognate immune system against cancer cells. Today, only three TLR agonists are approved by FDA for use in humans: the bacillus Calmette-Guerin (BCG), monophosphoryl lipid A (MPL) and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) is mainly used as a vaccine against tuberculosis, but also for the immunotherapy of in situ bladder carcinoma. MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix®, a vaccine against human papillomavirus-16 and -18. Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy.

https://www.tandfonline.com/doi/pdf/10.4161/onci.20931

Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy.

Summary Tumor antigen-induced inhibition of leukocyte adherence was adapted and modified for use in glass test tubes for the study of cell-mediated antitumor immunity to human adenocarcinoma of the breast. Peripheral blood leukocytes from 40 of 47 patients with proven breast cancer responded to an antigenic extract of breast cancer with significant leukocyte adherence inhibition, whereas only 2 of 32 controls showed a response. Further, 7 patients with histologically proven benign breast disease did not react to the breast adenocarcinoma extract, indicating that only breast cancer patients have leukocytes sensitized to the breast cancer antigen. The cell-mediated antitumor response of the breast cancer patient was dependent on the stage of the cancer, and patients with disseminated cancer had decreased responsiveness. In fact, 4 of 7 breast cancer patients who had no response in the assay had disseminated breast cancer. Also, surgery and irradiation depressed leukocyte adherence inhibition responsiveness. Chromatographic fractionation on Sepharose 4B of the breast cancer extract showed that the antigenic component was greater than 10 6 daltons. The responsive cell in the assay interacts directly with the tumor antigen, and as a result subsequent adherence to glass is inhibited. The assay described is a comparatively simple and sensitive technique for demonstrating cell-mediated antitumor immunity and appears to be immunologically specific.

https://cancerres.aacrjournals.org/content/canres/35/9/2571.full.pdf

Cell-mediated Antitumor Immunity in Breast Cancer Patients Evaluated by Antigen-induced Leukocyte Adherence Inhibition in Test Tubes

Results of administering B.C.G. to patients with melanoma.

We have used the leukocyte migration technique to examine the leukocytes of 138 breast cancer patients and 157 control donors for sensitization to breast carcinoma associated antigens. A majority of breast cancer patients (54%) showed sensitization while only 15% of the control donors reacted. Reactions were as frequent with autologous combinations of antigen and leukocytes as with homologous combinations, suggesting that transplantation antigens are relatively unimportant in the system and that breast cancers share structurally similar antigens. Reactions were less frequent with leukocytes from patients who had visceral metastases; however, patients with local recurrences were as frequently reactive as those with localized disease. Extracts of mastopathic breasts and fibroadenomas infrequently inhibited the leukocytes of cancer patients and of control donors. Macroscopically normal breast from the tissue around breast cancers may contain antigens similar to the tumour-associated antigens.

Sensitization to tumour-associated antigens in human breast carcinoma.

We have examined 111 cancer patients and 111 control individuals for general immunocompetence (haematological values, “recall” antigen skin tests, PHA and PPD induced lymphocyte transformation, serum Ig levels and lymphocyte subpopulations), for evidence of sensitisation to tumour-associated anti-tigens (leucocyte migration test, serum inhibition of autologous leucocyte migration, lymphocytotoxicity, membrane immunofluorescence and immune adherence) and for evidence of continuing immune reactions (alterations of complement components and anti-complementary activity). Major differences between the cancer patients and controls were demonstrated by several tests of sensitisation and these also detected differences between patients with and without metastases. The only differences detected between cancer patients and controls by the tests of general immunocompetence were in serum IgG and IgA (higher in the cancer patients) and lymphocyte subpopulations (“active” T, autorosetting lymphocytes and lymphocytes forming “super-rosettes” increased in cancer patients). In a comparison of cancer patients with and without metastases, patients with metastases were less often reactive to the Candida DHS and streptokinase-streptodornase antigens and had raised circulating Fc positive cells. Abnormalities of the individual components of complement occurred in about half the cancer patients, but were equally common in those with and without metastases. Serum anti-complementary activity was very rarely detected. The tests of specific sensitisation correlated reasonably well but correlations of tests of general immunocompetence were infrequent.



Une etude de l'immunologie des malades cancereux



Nous avons examine 111 cancereux et 111 temoins du point de vue de leur immunocompetence generale (valeurs hematologiques, tests cutanes avec des antigenes “de rappel”, transformation des lymphocytes induite par les PHA et PPD, niveau d'lg dans le serem et sous-populations de lymphocytes), de leur sensibilisation aux antigenes associes a la tumeur (epreuve de migration des leucocytes, inhibition seique de la migration des leucocytes autologues, lymphocytotoxicitd, immunojuorescence de la membrane et immuno-adhdrence), et de la persistance de leurs reactions immunitaires (alterations des composants du complement et activite anticomplimentaire). Plusieurs tests de sensibilisation ont mis en tvidence des diffirences importantes entre les cancereux et les temoins ainsi quentre les malades presentant des metastases ou n'en presentant pas. Les seules differences decelees entre 1es cancereux et les temoins au moyen des tests d'immunocompttence gPnPrale concernaient 1'IgG et 1'IgA seriques (plus elevees chez les canceeux) ainsi que les sous-populations de lymphocytes (les celfules T “actives”, les lymphocytes formant des autorosettes et les lymphocytes formant des “super-rosettes” sont plus nombreux chez les cancereux). Lors d'une comparaison entre les cancereux avec ou sans metastases, on a constate que les premiers reagissent moins frequemment aux antigenes Candida DHS et Streptokinase-streptodornase et qu'ils possedent davantage de cellules circulantes Fc-positives. Des anomalies des composants du complement ont ete observees chez la moitie environ des cancereux, mais elles etaient aussi frequentes chez ceux qui presentaient des metastases que chez ceux qui n'en presentaient pas. On a tres rarement decele une activite anti-complementaire dans les serums. Les tests de sensibilisation specifique sont en assez bonne correlation mais on a rarement observe des correlations entre les tests d'immunocompetence generale.

An examination of the immunology of cancer patients.

Sera from 38 of 89 melanoma patients, 4 of 15 patients with other cancers and 3 of 43 control donors inhibited the migration of autologous leukocytes. Sera from patients with clinically detectable metastatic disease and from the recipients of BCG were most frequently inhibitory. Autologous sera from 31 of 71 melanoma patients and 3 of 31 control donors increased the leukocyte migration inhibition induced by formalinized melanoma cells. This activity occurred in sera from patients at all stages of malignancy, whether bearing detectable tumour or not and whether receiving BCG or not. Abrogation of tumour-cell-induced leukocyte migration inhibition by serum was less frequent, occurring with 8 of 71 melanoma patients (6 Stage III, 1 Stage I and 1 Stage II) and no control sera. Preincubation of formalinized tumour cells had no effect on their activity in the leukocyte migration assay but the preincubation of melanoma leukocytes with either autologous serum or foetal calf serum inhibited leukocyte reactivity in around 50% of tests. However, this was also seen with control leukocytes and the effect appears to be immunologically non-specific.



Inhibition De La Migration Des Leucocytes Par Des Serums De Sujets Cancereux



Le serum de 38 des 89 malades atteints de melanome, de 4 des 15 sujets atteints d'autres cancers et de 3 des 43 temoins a inhibe la migration des leucocytes autologues. Le serum des malades atteints de cancer metastatique cliniquement decelable et des receveurs de BCG avait tres frequemment cet effet inhibiteur. Le serum autologue de 31 des 71 malades atteints de melanome et de 3 des 31 temoins accroissait l'inhibition de la migration des leucocytes induite par les cellules de melanome formolees. Cette activite a ete observee dans le serum des malades a tous les stades de l'evolution maligne, qu'ils portent ou non une tumeur decelable et qu'ils recoivent ou non du BCG. Il est moins frequent que le serum supprime l'inhibition de la migration des leucocytes induite par les cellules tumorales, puisque cet effet n'a ete observe que dans 8 des 71 cas de melanome (6 au stade III, 1 au stade I et 1 au stade II) et dans aucun des serums des temoins. La pre-incubation de cellules tumorales formolees n'a pas d'effet sur leur activite dans l'epreuve de migration des leucocytes, mais la pre-incubation des leucocytes de malades atteints de melanome avec du serum autologue ou du serum de fœtus de veau inhibe la reactivite des leucocytes dans environ 50% des tests. Toutefois, ce phenomene apparaǐt aussi avec les leucocytes des temoins et semble immunologiquement non-specifique.

Catherine E. Ross

Papers

Results of administering B.C.G. to patients with melanoma.

Sensitization to tumour-associated antigens in human breast carcinoma.

An examination of the immunology of cancer patients.

Leukocyte migration inhibition by cancer patients' sera.

The Mechanism of Tumour Cell Induced Inhibition of Human Leucocyte Migration