Objective Evidence Of Tumor Regression Research Articles

Abstract 5588: Clinical and pharmacodynamic responses to a modified whole tumor cell immunotherapy in patients with advanced breast cancer from two phase I-IIa trials

Abstract SV-BR-1-GM is a GM-CSF secreting breast cancer cell line that also expresses HLA class I & II antigens. Irradiated SV-BR-1-GM is used in a regimen including pre-dose low-dose cyclophosphamide and post-dose local interferon-α2b. The SV-BR-1-GM regimen has been used alone (“Monotherapy” study ClinicalTrials.gov NCT03066947) and in combination with immune checkpoint inhibitors (ongoing combination study ClinicalTrials.gov identifier NCT03328026). Here we report regression of metastatic breast cancer and pharmacodynamic analysis with immunologic correlates. 23 patients with advanced breast cancer refractory to standard therapies were treated with the SV-BR-1-GM regimen in the monotherapy trial with cycles every 2 weeks for the first month and then monthly. The combination study is evaluating the SV-BR-1-GM regimen with checkpoint inhibitors (PD-1 inhibitors pembrolizumab or INCMGA00012) with cycles every 3 weeks (11 patients have been dosed to date). Pharmacodynamic analyses include delayed-type hypersensitivity (DTH), antibodies against SV-BR-1 (precursor of SV-BR-1-GM), blood lymphocyte proliferation (determined using flow cytometry), circulating cytokines in sera and cytokine secretion (Luminex based assays) following stimulation with peptides of antigens expressed in SV-BR-1-GM cells (HER2 and PRAME). In the monotherapy study, tumor regression was seen in 3 patients. 21 patients developed measurable DTH signifying cellular immunity. Blood lymphocytes from responders after treatment showed increased proliferation and cytokine secretion (GM-CSF, IL-2, IL-21) - following stimulation with HER2 and PRAME peptides. Differential serum cytokine levels were observed (CD40L, MCP-1, IL-1RA) in 5 patients. Increased antibody levels compared to baseline were observed in 6 of the 12 patients assessed. Patients with objective tumor regression had the most pronounced responses. In the combination therapy study, 2 patients have shown objective evidence of tumor regression, including one patient with liver metastases, which decreased by 25%, and one patient with adrenal and dural metastases (29% reduction in target lesion). Both patients had Grade II tumors, similar to the tumor from which SV-BR-1-GM was derived. These observations confirm the ability of the SV-BR-1-GM regimen to elicit regression of far advanced refractory metastatic breast cancer. No serious toxicities clearly attributed to the SV-BR-1-GM regimen were observed. Pharmacodynamic analysis of humoral and cell-mediated immune responses showed notable upregulation, the strongest responses being seen in those with measurable clinical regression. Patients with Grade I or II tumors appeared more likely to respond. Citation Format: Vivekananda G. Sunkari, Jacqueline Galeas, Shaker R. Dakhil, Jarrod Holmes, Saveri Bhattacharya, Carmen J. Calfa, Ajay Kundra, Daniel L. Adams, Diane DaSilva, George E. Peoples, Charles L. Wiseman, William V. Williams, Markus D. Lacher. Clinical and pharmacodynamic responses to a modified whole tumor cell immunotherapy in patients with advanced breast cancer from two phase I-IIa trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5588.

Results from a Phase 1 Study of Sodium Selenite in Combination with Palliative Radiation Therapy in Patients with Metastatic Cancer

In preclinical studies, selenite had single agent activity and radiosensitized tumors in vivo. Here we report results from a Phase 1 trial in 15 patients with metastatic cancer treated with selenite (5.5 to 49.5 mg) orally as a single dose 2 hours before each radiation therapy (RT) treatment. Patients received RT regimens that were standard of care. The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11–78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT.

The novel Ras antagonist, farnesylthiosalicylate, suppresses growth of prostate cancer in vitro

The majority of men with advanced prostate cancer (PCa) respond to androgen deprivation therapy (ADT) with objective evidence of tumor regression. However, these tumors will regrow in the presence of low-androgen levels after 12-18 months. Regrowth after ADT is associated with upregulation of growth factor (GF) mediated pathways. The compound farnesylthiosalicylate (FTS), a specific antagonist of the 21 kDa Ras protein, suppresses GF signaling and it might be a useful therapy against advanced PCa. We measured androgen and GF dependent growth of androgen dependent LNCaP and androgen hypersensitive CWR-R1 PCa cells in response to specific inhibitors of GF pathways, including FTS. Inhibition of GF mediated signaling and cell-cycle pathways was confirmed by Western blotting of extracts from treated cells. Both LNCaP and CWR-R1 cells were dependent on GF signaling pathways for cell growth. FTS, as well as suppressing cell growth, inhibited GF signaling pathway activity and reduced the levels of E2F1, p-Rb, and p-cdc2, all GF dependent mediators of cell-cycle progression. These data suggest that FTS might be a useful agent against PCa that has relapsed after ADT.

Treatment of hormone‐refractory stage D carcinoma of prostate with coumarin (1,2‐benzopyrone) and cimetidine: A pilot study

The combination of coumarin (1,2-benzopyrone) and cimetidine has been reported to render objective tumor regressions among patients with metastatic renal cell carcinoma and malignant melanoma. Subsequently, a pilot trial was conducted to evaluate this regimen for the treatment of stage D hormone-refractory carcinoma of the prostate. Patients received coumarin 100 mg orally as a single daily dose for 14 days; on day 15 cimetidine 300 mg four times daily was added, and both drugs were continued until progression of disease. Fourteen patients with advanced prostate cancer were treated. Nine patients had evaluable disease only, whereas five patients had both measurable and evaluable disease. All patients had bone metastases. Although there was no objective evidence of tumor regression, three patients (with evaluable disease only) experienced significant improvement in bone pain with decreased analgesic use that persisted until disease progression at 3, 5.5+, and 9 months. Although coumarin caused no symptomatic or organ dysfunction toxicity, one elderly patient experienced reversible mental confusion from cimetidine. Coumarin and cimetidine, at the dose and schedule described, are not effective for the treatment of advanced prostate cancer. However, the results of laboratory investigations suggest that further clinical trials of coumarin, at higher doses, may be warranted for the treatment of this disease.

Cisplatin and radiation therapy for locally advanced squamous cell carcinoma of the lung

A pilot study was initiated to test the safety and efficacy of the simultaneous administration of high-dose cisplatin and irradiation in patients with locally advanced squamous cell carcinoma of the lung. Cisplatin was administered at 100 mg/m2 on Days 1 and 21 and was continued at 20 mg/m2 once a week to the completion of radiation therapy. Irradiation was begun on Day 22 and was administered 5 days a week for 6 weeks at a rate of 200 cGy per day to a total of 6000 cGy to the primary site, using a shrinking field technique. Of the 13 patients so treated, all but one showed objective evidence of tumor regression according to chest x-ray. Six patients are still alive from 12 to 37 months after the start of treatment, including four who are asymptomatic and without apparent tumor and two with persistent local disease. Of the seven patients who died, four had metastatic disease (including one with local recurrence as well), one (who had been resistant to therapy) had persistent local disease, and two died too early to allow comment on efficacy (although autopsy in one case showed no evidence of locoregional tumor). This program is both active and tolerable, and deserves further study.

Phase I study of multiple dose intramuscularly administered recombinant gamma interferon.

We report the results of a phase I study of the tolerance and biologic activity of intramuscularly (IM)-administered recombinant interferon-gamma (rIFN-gamma). Forty-four patients with metastatic cancer were given rIFN-gamma at doses ranging from 0.01 to 2.5 mg/m2/d for 42 days. The most common side effects were fever, flulike symptoms, night sweats, and granulocytopenia. The maximum tolerated dose was 0.5 mg/m2/d. Administration of rIFN-gamma resulted in modulation of immune system functions, including induction of major histocompatibility complex-associated antigens on blood leukocytes, an increase in blood surface immunoglobulin-bearing B cell and natural killer (NK) cell number, and NK cell cytotoxicity. Serum lysozyme, determined as an estimate of tissue macrophage activity, also increased. Serum assays for anti-interferon antibodies were negative in all patients. Five of eight evaluable patients with lymphoproliferative disorders showed objective evidence of tumor regression consisting of partial responses (two patients), and minor responses (three patients). These data suggest that further phase II studies of IM-administered rIFN-gamma are indicated.

Phase II trial of 4'-deoxydoxorubicin (esorubicin) in hormone resistant prostate cancer.

Fifteen patients with hormone resistant advanced prostate cancer were treated with anthracycline analog 4'-deoxydoxorubicin (Esorubicin). No patient had objective evidence of tumor regression. Six patients (40%) were classified using the National Prostatic Cancer Project criteria as having stable disease after two courses of therapy. Treatment was associated with significant hematologic toxicity with 50% of patients experiencing grade III or IV neutropenia. Clinical cardiac toxicity was not observed. Further trials of 4'-deoxydoxorubicin do not appear to be warranted in advanced prostate cancer.

Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients.

Sixteen patients with advanced cancer were treated with recombinant-DNA-produced pure leukocyte A interferon (IFLrA) intramuscularly in doses ranging from 3 to 198 X 10(6) units. with interval periods of 72 to 96 hours between doses. At the two lowest doses of 3 and 9 million units, there was a cross-over evaluation between IFLrA and partially pure leukocyte interferon (IFN-C) produced from human cells. THe maximum observed serum concentration of IFLrA measured by enzyme immunoassay and bioassay increased with increasing doses. The mean serum concentrations of IFLrA and IFN-C were similar. Clinical effects produced by IFLrA and IFN-C were similar, including fever, chills, myalgias, headache fatigue, and reversible leukopenia and granulocytopenia. Eight patients had transient and mild numbness of the hands or feet, or both. Three patients developed low titers of antibody to IFLrA, Seven of 16 patients showed objective evidence of tumor regression during the study.

A phase I trial of continuous infusion VP16-213 (etoposide).

Since there appears to be a schedule dose relationship for VP16-213, the current dose seeking study of 5 day continuous infusion was initiated. Patients not candidates for other treatments were started at 75 mg/m2/day X 5. Eight patients had prior chemotherapy, eight had radiotherapy plus chemotherapy and one patient had prior interferon. The median age was 53 (range 23-65) and the median performance status was 60 (range 50-90). Seventeen patients received 20 courses; two at 75 mg/m2/day, seven at 100 mg/m2/day, ten at 125 mg/m2/day, and six at 150 mg/m2/day. The major toxicity was hematologic and median WBC count nadirs (ranges) were respectively: 3.5 (2.3-4.7) X 10(3)/microliters, 1.6 (0.2-3.4) X 10(3)/microliters, 2.4 (0.1-3.6) X 10(3)/microliters, 0.4 ( less than 0.1-0.7) 10(3)/microliters. Platelet count nadirs were respectively: 150, 78 (20-189), 138 (26-326), 16 (9-88) X 10(3)/microliters. The median days to WBC nadir and recovery and did not vary with dose and were 15 (9-21) and 24 (19-38) respectively. Median days to platelet count nadir were 12 (10-29) the recovery 24 (20-38) and did not vary with dose. Non-hematologic toxicities included mild nausea and vomiting, mild mucositis on six courses, diarrhea with two courses and fever during granulocytopenia during seven courses. Three patients manifested evidence of myocardial diseases two with infarction and one with congestive failure during treatment. Two patients showed objective evidence of tumor regression, one patient with seminoma and one patient with renal cell carcinoma. The latter response was short. The current studies demonstrate that high dose continuous infusion VP16-213 is tolerable with acceptable toxicity using doses up to 125 mg/m2/day (625 mg/m2 over 5 days).

The Response of Metastatic Adenocarcinoma of the Prostate to Exogenous Testosterone

In a retrospective review the response of 67 patients with metastatic adenocarcinoma of the prostate to the administration of exogenous testosterone was analyzed. Among 52 patients in whom objective and/or subjective responses were evaluable 45 experienced unfavorable responses. There was prompt regression of most unfavorable responses with testosterone withdrawal. The duration of treatment required to evoke an unfavorable response was related to the clinical status of the patient. Twenty-five per cent of patients with symptomatic metastases who had received no prior treatment, 36 per cent in symptomatic remission after endocrine therapy and 94 per cent with symptomatic relapse after endocrine therapy experienced unfavorable responses within 30 days of treatment. No patient had objective evidence of tumor regression during testosterone therapy but 7 patients, 6 with remission and 1 untreated, experienced symptomatic benefit. We conclude that the response of patients with metastatic prostate cancer to exogenous testosterone is related to the mass and endocrine treatment status, and that exogenous testosterone can stimulate prostatic neoplasms that proliferate in the absence of normal endogenous testosterone levels.

Combination chemotherapy in invasive thymoma. Role of COPP

Combination chemotherapy consisting of cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) was administered to 5 patients with invasive lymphoepithelial thymoma. Objective evidence of tumor regression was seen in 4 patients. Given prior to preoperative radiation therapy, COPP produced partial remissions in 2 patients, making possible smaller radiation treatment fields. Two patients with pleural involvement when first seen, achieved tumor regression when COPP was given prior to radical radiation therapy. One of these patients remains disease-free at 34 months; the other succumbed to pneumonitis. One patient, presenting with pleural metastasis three years after undergoing incomplete resection of thymoma, failed to respond to treatment. Combination chemotherapy with COPP can produce objective regression of invasive lymphoepithelial thymomas which may be useful in the preoperative management of selected cases, as well as in the management of unresectable or metastatic disease.

Mitotane ( o, p′-DDD)

Summary Mitotane ( o, p′ -DDD) is an isomer of the insecticide DDD and a chemical congener of the insecticide DDT. Its use in the treatment of unresectable adrenal cortical carcinoma was based upon the initial observation of Nelson and Woodward that dogs given the insecticide DDT showed necrosis and atrophy of the adrenal cortex. Mitotane exerts a direct cytotoxic effect on the fascicular and reticular zones of the adrenal cortex. Following intravenous and oral administration, varying concentrations are demonstrable in different tissues and organs like the adipose tissue, adrenals and liver. The compound is excreted in the stool and urine. Clinical trials in 301 patients with inoperable adrenal cortical carcinoma have demonstrated its therapeutic efficacy characterized by objective evidence of tumor regression, decreased steroid excretion and improvement in subjective symptomatology. Toxicities from mitotane are referrable to the gastrointestinal, neuromuscular and dermal systems. Less common side effects involve the eyes, gonitourinary and cardiovascular systems. They are reversible upon reduction of the dose or discontinuation of the drug. The recommended dose schedule is to start the patient at 8–10 g/day in divided doses. The dose should be reduced if severe side effects develop. It has been suggested that steroid replacement therapy be administered concomitantly with the start of mitotane treatment (12, 19) rather than after the appearance of signs of adrenocortical insufficiency or when urinary corticoid excretion is low (2). Though there are no reported data on the use of mitotane following surgical removal of an adrenocortical carcinoma, its potential value as an adjuvant agent (inasmuch as some of these patients subsequently develop recurrence or metastases) deserves some consideration in the future.

Spinal chordomas

A series of 54 patients with spinal chordomas were treated at Memorial Sloan-Kettering Cancer Center between 1949 and 1976. Thirty-six lesions were located in the sacrococcygeal region and 18 involved the vertebral column at a higher level. The male to female ratio was 35:19. Vertebral chordomas generally occurred in a younger age group. Our radiological findings suggest that there is marked soft-tissue extension anterior to the vertebral column at the time of initial diagnosis. Eleven of 18 vertebral chordomas and 10 of 36 sacral chordomas were found to have disseminated metastases during their course. Analysis of the various modes of therapy reveals that the median survival for both groups is approximately 6 years. However, the 5-year survival for the sacrococcygeal group was 66% as opposed to 50% for the vertebral group. Radiation therapy produced significant palliation but objective evidence of tumor regression was difficult to assess. Chemotherapy in a small number of patients did not have any effect on the tumor. With the advent of computerized tomography scanning, further studies should be done to document the response of this tumor to radiation therapy.

Combination chemotherapy with bleomycin, cyclophosphamide and dactinomycin for the treatment of osteogenic sarcoma.

Thirteen patients with osteogenic sarcoma were treated with multiple drug chemotherapy consisting of bleomycin, cyclophosphamide and dactinomycin. The dosage schedule used was: bleomycin 12 mg/m2/day, cyclophosphamide 600 mg/m2/day, and dactinomycin 450 microgram/m2/day. All drugs were given intravenously for two consecutive days. Treatment was repeated every 2 weeks. Toxicity included severe nausea and vomiting (managed with antiemetics and intravenous hydration) and manifestations of bone marrow depression. Of 13 patients, eight were previously treated with high dose methotrexate with citrovorum factor rescue, cyclophosphamide and Adriamycin. Of these eight, three patients had objective evidence of tumor regression (37.5%). Five of five previously untreated patients had objective evidence of tumor regression. The overall response rate in osteogenic sarcoma patients to BCD was 61.5%. The combination of BCD appears to be more active against osteogenic sarcoma than cyclophosphamide alone or Adriamycin alone. The relative safety with which BCD can be administered makes this combination a valuable adjunct to high dose methotrexate with citrovorum factor rescue and Adriamycin in the treatment of osteogenic sarcoma.

Treatment of advanced cancer with active immunization.

Forty-two patients with advanced cancer of various types were actively immunized with autologous tumor coupled to rabbit gamma-globulin. Only one of the 36 evaluable patients had objective evidence of tumor regression. A partial immunologic survey showed no evidence of delayed hypersensitivity and minimal evidence of humoral antibodies to tumor extract. Toxicity was limited to local immediate hypersensitivity reactions to rabbit gamma-globulin and granulomatous nodules at the site of the intradermal vaccine inoculations. There was no evidence of tumor growth enhancement. This therapeutic approach of active tumor immunization did not enhance an immunologic tumor rejection mechanism.

Closed pelvic perfusion: A new approach to the problem of advanced gynecologic malignancy

Isolated pelvic perfusion was carried out in 20 patients with advanced nonresectable disease limited to the pelvis. The “closed” method, which does not necessitate abdominal operation, was used.At the time of writing, 6 of the 13 post-operative survivors are alive 6 weeks to 16 months after perfusion. Six patients survived more than 5 months after perfusion.Thirteen patients lived long enough to allow objective and subjective assessment. In all 13, some objective evidence of tumor regression was obtained, and in 11 cases, a variable degree of pain relief was achieved.

Acute fatal hypercalcemia. A complication in estrogen therapy of metastatic breast cancer.

ESTROGEN has proven to be of great value in the treatment of metastatic mammary carcinoma. Increased well-being, symptomatic relief, objective evidence of tumor regression, and even prolonged survival have been obtained in the face of advanced local and generalized carcinomatosis. This agent is particularly effective after the tenth postmenopausal year. Estrogen has been more effective than androgen. The toxic side effects of estrogen therapy are not inconsequential. Gastrointestinal upset, pigmentation, urinary frequency, vaginal bleeding, saltretention edema, and hypercalcemia have been observed. Hypercalcemia, in particular, may be quite dangerous. In 1949, Hermann and others reported 4 cases of lethal hypercalcemia following the administration of androgen and estrogen. Since that time admonitions regarding this possible side effect have appeared repeatedly in the literature dealing with sex steroid therapy of carcinomatosis. Two recent hypercalcemie complications of estrogen therapy at the Breast Service of the Francis Delafield Hospital prompted a review of our experience