Treatment of Metastatic or High-Risk Solid Cancer Patients by Targeting the Immune System and/or Tumor Burden: Six Cases Reports

Abstract

This article summarizes the histories of six patients with different solid tumors treated with a new strategy based on tumor burden reduction and immune evasion as potential targets. All six patients were at a high risk of relapse and were likely to have a minimal residual disease following conventional therapy: biochemical recurrence (BCR) following radical prostatectomy (RP) (two prostate cancers patients), removal of distant metastases (one colorectal and one breast cancer), and complete response (CR) of distant metastases to conventional therapy (one breast cancer and one esophageal–gastric junction cancer). Four of the patients, two after RP and BCR, one after removal of a single pulmonary metastasis from breast cancer, and one after CR to chemotherapy of peritoneal metastases and ascites from an esophageal–gastric junction primary cancer, regularly received cycles of a new drug schedule with the aim of inhibiting immune suppression (IT). In these four patients, preliminary laboratory tests of peripheral blood suggested an interleukin (IL)-2/IL-12 mediated stimulation of cellular immune response with a concomitant decrease in vascular endothelial growth factor (VEGF) immune suppression. The fifth case was a breast cancer patient with distant metastases in CR, while receiving beta-interferon and interleukin-2 in addition to conventional hormone therapy. To date, all five patients are alive and doing well and they have been unexpectedly disease-free for 201 and 78 months following BCR, 28 months following the removal of a single pulmonary metastases, 32 months following CR to chemotherapy of peritoneal metastases and ascites, and 140 months following diagnosis of multiple bone metastases, respectively. The sixth patient, who had colorectal cancer and multiple synchronous liver metastases and underwent nine surgical interventions for metastatic disease, although not disease-free, is doing well 98 months after primary surgery. Our six cases reports can be interpreted with the hypothesis that immune manipulation and/or a concomitant low tumor burden favored their clinical outcome.

Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy

“…Thus, any cancer type, independent of the currently pre-defined immunogenicity, has inducible immunogenicity proportional to the capability of the available therapeutic means to counteract tumor growth and immune inhibition. The surprisingly promising findings observed in our 2:1 control-case retrospective observational study support this notion; this, along with other findings, suggests that low tumor burden and/or tumor cell quiescence are important conditions favoring a successful immune manipulation [ 190 , 191 ]. This assumption and the absence of therapies to cure the overt metastatic disease suggest concentrating any effort during MRD where both conditions coexist.…”

“…This therapeutic strategy could significantly decrease the rate of relapses in the first 5–6 years with a huge saving of expenses by the Health National Services and, more importantly, of lives and pains. Based on our and others’ preliminary work and pilot studies [ 145 , 191 , 220 ], specific clinical trials should be easy to design, and safe and cheap to carry out. Multinational drug companies do not have an interest to sponsor such investigational trials as the proposed schedules include repurposed drugs without patents and at low cost.…”

“…( B ) Additional cyclic immunotherapy (IT) alternated with prolonged conventional adjuvant chemotherapy (CT) in breast cancer other than luminal A and at high risk of relapse. IISS: inhibiting immune suppression; IMMD CT: immune modulatory CT. ** For the schedule see reference [ 191 ], this IISS therapy is alternated with four cycles (3 months overall) of conventional IMMD CT; DX: desamethasone; CY: cyclophosphamide; COX-2i: COX-2 inhibitor; Rt: retinyl palmitate; alpha-Tc: alpha tocopheryl acetate; DOXO: doxorubicin; PTX/DX: paclitaxel/docetaxel; CAPE: capecitabine; CBDCA/CDDP: carboplatin/cisplatin; PMN borders.…”

“…The host immune system is probably more robust in the early disease due to the limited cancer burden and the major effectiveness in triggering an antitumor immunologic response to new antigens” [ 43 ]. We have also recently reported on one breast cancer patient with minimal residual disease (MRD) at high risk of relapse following radical resection of a single lung metastasis and two others with biochemical recurrence after radical prostatectomy who received successful immune therapy [ 191 ]. In conclusion, in addition to a prolonged G0-G1 state, our findings along with others suggest a low or undetectable tumor burden for more successful tumor immune manipulation [ 157 ].…”

“…We carried out these or similar schedules for 5–6 years or until relapse with preliminary promising findings. Moreover, while the short cyclic CT administration makes it well tolerated [ 220 ], the proposed immune therapies did not show relevant AEs and irAEs [ 145 , 191 , 220 ].…”