The efficacy of sacituzumab govitecan and trastuzumab deruxtecan on stable and active brain metastases in metastatic breast cancer patients-a multicenter real-world analysis.

BACKGROUND: Fifteen to thirty percent of all patients with metastatic breast cancer (MBC) develop brain metastases (BCBMs). Recently, the antibody-drug conjugates (ADCs) sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) have shown to be highly effective in the treatment of MBC. However, there are only limited data whether these macromolecules are also effective in patients with BCBMs. We therefore aimed to examine the efficacy of SG and T-DXd in patients with stable and active BCBMs in a multicenter real-world analysis. PATIENTS AND METHODS: Female patients with stable or active BCBMs who were treated with either SG or T-DXd at three breast centers in Germany before 30 June 2023 were included. As per local clinical praxis, chemotherapy efficacy was evaluated by whole-body computed tomography and cranial magnetic resonance imaging at baseline and at least every 3 months according to local standards. Growth dynamics of BCBMs were assessed by board-certified neuroradiologists. RESULTS: Of 26 patients, with a median of 2.5 prior therapy lines in the metastatic setting (range 2-15), 12 (43%) and 16 (57%) patients received SG and T-DXd, respectively. Out of the 12 patients who received SG, 2 (17%) were subsequently treated with T-DXd. Five out of 12 (42%) and 5 out of 16 (31%) patients treated with SG and T-DXd, respectively, had active BCBMs at treatment initiation. The intracranial disease control rate was 42% [95% confidence interval (CI) 13% to 71%] for patients treated with SG and 88% (95% CI 72% to 100%) for patients treated with T-DXd. After a median follow-up of 12.7 months, median intracranial progression-free survival was 2.7 months (95% CI 1.6-10.5 months) for SG and 11.2 months (95% CI 7.5-23.7 months) for T-DXd. CONCLUSIONS: SG and T-DXd showed promising clinical activity in both stable and active BCBMs. Further prospective clinical studies designed to investigate the efficacy of modern ADCs on active and stable BCBMs are urgently needed.

Antitumor effect of sublethal irradiation caused by its tolerance abrogating capacity.

After the resection of methylcholanthrene-induced fibrosarcomas, representing 1--2% of total body weight, "R" rats were immunized with glutaraldehyde-fixed tumor cells, irradiated sublethally [0.1419 C kg-1 (550 R)], and restored immunologically by thymus, spleen and bone marrow cells. Afterwards, 87.5% of them were able to reject a viable challenge cell graft of 1 X 10(5) cells. Sublethal irradiation alone had the same effect, reflected by 90% of rats rejecting the grafts. Five control lots were run. They showed that none of the treatments, applied to "tumor-resected" animals could provide normal animals with the same defense capacity. Results point to the decisive role of the transient presence of the tumor in the host and of the sublethal irradiation in restoration of its defense capacity. Role of partial tolerance, in producing the host's immune inhibition, and of the capacity of irradiation to abrogating it, are discussed.

Suppression of immune anti-tumor lymphocytes by macrophages of advanced tumor bearing rats, across a cell impermeable membrane.

In experiments using double and triple chamber cultures it was demonstrated that suppressive macrophages from advanced T8-Guérin tumor (diameter 5--6.5 cm) bearing rats produced a dialysable factor which suppressed the killer activity of lymphocytes from non-advanced T8-Guérin tumor (diameter 0.5--0.7 cm) bearing rats, as well as from nonadvanced h 18R tumor bearing rats and from Ehrlich ascites bearing mice, against T8-Guérin ascitic cells and, respectively, against h 18R ascitic and Ehrlich ascitic cells. The dialysable suppressive factor inhibits immune lymphocytes but has no effect on the lymphotokin itself already produced.

Effects of tumor cell culture supernatants on macrophages.

It is proved that supernatants of various tumor cell cultures, as well as cell-free ascitic fluid and sera from tumor bearing animals induce the detachment of macrophages from glass, the loss of their ability to form pseudopodia, the inhibition of their migration and the permeability alteration of their membranes. The cytotoxic effect is not produced by normal tissues, excepting placenta. The effect of tumor cell culture supernatants depends on the characteristic evolution time of each tumor; irradiation diminishes this effect. The involvement of macrophages in immune surveillance and response makes the results interesting for the tumor-host immune relation.

Some data concerning immune processes in concomitant tumor immunity experimental models. Comparative in vivo and in vitro investigation I. In vivo experiments.

Concomitant tumor immunity evinced by C57BL/6 mice, bearing a MC-induced sarcoma, was evaluated by graded challenge doses for different primary tumor sizes (2-3,4-6,8-12% tumor weight of the total body weight TW/TBW). 100% of mice bearing tumors, representing 2--6% of total body weight, rejected doses from 0.2--1 X 10(4) cells. The gradual curtailment of the concomitant tumor immunity, depending on increasing TW/TBW ratio, could be evaluated, using adequately increasing challenge doses. The immune equipotency of the whole s.c. body area, the failure to modify the concomitant tumor immunity by drainin node excision and the demonstration of its dependency upon the total challenge-dose and its independency upon fractionated multilocular inoculation of the challenge, showed clearly that the concomitant tumor immunity is a local expression of general immunity. The experimental model allows a valuable biological assessment of the tumor-beareer immune status and represents likewise an adequate tool for immunotherapeutic effects estimation.

Some data concerning immune processes in concomitant tumor immunity experimental models. Comparative in vivo and in vitro investigations II. In vitro experiments.

The humoral and cellular immune status of C57BL/6 male mice and "R" male rats bearing MC-induced sarcomas were investigated in vitro, using 51Cr-releasing and mixed hemadsorption assays. Analysis was performed on mice subjected to concomitant tumor immunity (CTI) model experiments or bearing primary tumors of different sizes, that was done also in rats. Chromatographic fractions, assumed to contain tumor specific antigens, antibodies or antigen-antibody complexes were identified by their absorption capacity upon specially prepared syngeneic immune sera. Free antibody and antigen-antibody complexes, accompanied with a weak cell mediated immunity (CMI) were correlated with efficient CTI in 2--3% TW/TBW tumor bearers. Homoral immunity (HI) showed sometimes an important increase after challenge administration. High levels of free antigen and antigen-antibody complexes, lack of antibodies and CMI were correlated with CTI absence in huge tumor bearers, representing 30--37% of total body weight. Conditions determining variability of results reported by different authors and the possible mechanisms by which serum immune factor may impair the tumor bearer's immune status are discussed.