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Solid human tumors were dissociated with collagenase, cultured for 16-48 hours, and harvested for cytogenetic preparation. Of the 19 tumors used, 14 showed sufficient numbers of metaphases to be useful for chromosome analysis.
A computer program has been developed to quantitatively evaluate changes in tumor growth rates of a solid tumor model (hepatoma 3924A) after a series of radiation doses from 375 R to 3750 R. The computer-derived growth curves are simulated from the volumes of the individual tumors rather than from the mean tumor volume at any specific time point after treatment. The ability to generate data from a family of tumor growth curves permits a more precise evaluation of therapeutic effects on tumors than can be obtained with conventional methods. The quantitative determination of equivalent amounts of radiation needed to produce comparable 5-fluorouracil-induced changes in tumor growth rate has been made. The ability to determine quantitatively radiotherapeutic and chemotherapy equivalents on these solid tumor models has direct implications in regard to our effort to improve the treatment of cancer. At present no specific solid tumor or groups of solid tumors have provided all of the necessary information for clinical utilization in therapeutic scheduling of different forms of cancer treatment. Since solid tumors comprise the majority of human cancer, one of the primary objectives of these studies has been the establishment of a solid tumor model that could serve both as a system for devising improved therapeutic scheduling and for a better understanding of solid tumors.
Single, large doses of adriamycin, cyclophosphamide and 5-fluorouracil (5-FU) have been compared to the same amount of drug given in divided doses daily over a 3 or 5 day period in a solid tumor model which metastasizes to the regional lymph nodes and lungs. No significant increase in life expectancy occurred following adriamycin or cyclophosphamide. However, a significant reduction in life expectancy occurred after 5 fractionated doses of 5-FU but not after the large single dose. The increase in mortality following fractionated doses of 5-FU is attributed to the prolongation of the onset of recovery of bone marrow. Tumor volume reduction following a single dose of each agent was equal to or greater than the fractionated doses. The results of these studies on this chemotherapeutically resistant solid tumor indicate that small daily fractionated doses of adriamycin, cyclophosphamide or 5-FU result in increased morbidity and mortality without therapeutic benefit in tumor control. The time sequence of recovery of the limiting organ of the host (i.e., bone marrow) is similar to the time sequence of recovery of the tumor. Large intermittent single doses of chemotherapeutic agents given following recovery of the host from a previous treatment would be expected to be less toxic to the host and equally effective in control of tumor growth. None of the 3 chemotherapeutic agents was successful in tumor eradication. Previous studies of this series have shown that the utilization of sequential chemotherapy combined with radiotherapy can be successfully used for eradication of another solid tumor which did not metastasize. A similar therapeutic strategy using sequential combined modality therapy should also be effective in the control of the primary H-4-II-E tumor as well as its metastatic dissemination. Information gained from these experimental studies should eventually provide information which should be helpful in the clinical management of chemotherapeutically resistant solid tumors in man.
Systematic chromosomal studies in solid tumors have been scanty (excepting meningiomas), because of the fact that it is difficult to obtain tumor material at desired times and only in about 10--15% of the cases adequate chromosome preparations are suitable with a direct technique or short term culture. A few facts that emerge from the study of various solid tumors are as follows: 1. modal number of chromosomes in parimary tumors tends to be lower that of metastatic; 2. certain chromosomes and chromosome regions are more susceptible for breakage to oncogenic conditions, hence, there is non-random involvement of certain chromosomes in human neoplasia and 3. certain chromosome changes are more often associated with metastatic spread than others.
An in vitro-in vivo system for screening potentially effective drugs against solid tumors is described. Drug toxicity to plateau-phase pulmonary adenoma cells is used as an in vitro screen for potential activity against solid tumors, since both plateau phase cultured cell populations and solid tumors are composed predominantly of nondividing cells. The effect of drugs with in vitro activity on the rate of appearance of urethan-induced adenomas on the lung surface of strain A mice in vivo is used to assess drug efficacy in the treatment of solid tumors, taking into consideration drug toxicity to and drug metabolism by the host. Arabinosylcytosine and hydroxyurea were ineffective against plateau phase cells in vitro, even at high concentrations (5 to 10 mg/ml), and did not affect pulmonary adenoma growth in vivo, even at toxic doses (arabinosylcytosine, 80 mg/kg; hydroxyurea, 800 mg/kg), as would be expected with these cell cycle-active drugs. Adriamycin, an effective agent against human solid tumors, was cytotoxic to plateau phase cultured cells (0% survivors at 1 mug/ml), and a dose of 2 mg/kg completely inhibited pulmonary adenoma growth in mice. Thus, this pulmonary adenoma bioassay would appear to effectively select for drugs which may be active against solid tumors in humans.
Wilms' tumor is the model of the treatment of a pediatric solid tumor. Initially it appeared that multi-modality therapy, consisting of transabodominal nephrectomy, post-operative radiation therapy to the tumor bed and adjuvant, single agent chemotherapy provided the highest likelihood of disease-free survival. The identification of important prognostic factors, such as histology, tumor weight, lymph node involvement and age at diagnosis has led to a re-examination of the treatment of Wilms' tumor. Future therapeutic developments will include the administration of less therapy to some well defined groups of patients, and the exploration of new programs for patients who have been demonstrated to have a poor prognosis using currently accepted treatment techniques.
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The frequency of solid tumors was evaluated in 628 consecutive patients with multiple myeloma who had been treated with various melphalan-prednisone combinations. Among those patients who lived at least 2 months, the incidence and diversity of second tumors were similar to those in normal persons of the same age and duration at risk. The diagnosis was usually made within 2 years after the start of chemotherapy for the myeloma. Long-term melphalan therapy did not seem to contribute to the pathogenesis of second solid tumors in patients with multiple myeloma.
BACKGROUND: Chimeric antigen receptor macrophage (CAR-Mφ) therapy has promising therapeutic potential in solid tumors, yet challenges remain in target compatibility and systemic toxicity. METHODS: In this study, we screened the CD47-scFv sequence of CAR-Mφ as the extracellular structure. We then constructed a classical CD47 CAR-Mφ incorporated the costimulatory domain of the α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component. Subsequently, we developed a tumor microenvironment (TME)-responsive CAR macrophage platform by the arginase 1 (Arg1) promoter to target CD47, a highly expressed but clinically challenging immune checkpoint in solid tumors. RESULTS: We found that anti-CD47-scFv-mediated macrophages can effectively kill tumor cells both in vivo and in vitro. Furthermore, by integrating an α1β1 integrin-mediated FcγRI signaling domain, CD47 CAR-Mφ exhibited superior antitumor activity in hCD47+4T1 and SGC-7901 cells in vitro, which demonstrated that the CD47 CAR-Mφ was effective against solid tumors. Subsequently, Arg1-mediated activated pArg1 CD47 CAR-Mφ exhibited strong cytotoxicity against target cancer cells. We further demonstrated TME-controllable CAR gene expression in situ and induced a significant regression of established tumors in vivo. Besides, TME-dependent activation of CD47 CAR Mφ reduced the cytotoxic killing effect on erythrocytes. CONCLUSIONS: Our findings confirmed that the TME-specific activation mechanism of pArg1 CD47 CAR-Mφ based on intrinsic Arg1 promoter reprogramming endowed CAR-Mφ to effectively mitigate erythrocyte toxicity while enabling safe multidose administration regimens. This Trojan horse-like CAR-Mφ system achieves tumor-specific activation while minimizing systemic toxicity, offering a novel strategy to expand CAR-Mφ applications for solid tumors.
The densities of viable EMT6 cells grown in vitro as monolayer exponential and plateau-phase cells or as multicell spheroids or in vivo as a solid tumor in BALB/c mice were determined with the use of isopyknic centrifugation in linear Ficoll gradients. Exponential cells banded at a density of 1.069 g/ml, whereas plateau-phase cells appeared at 1.073 g/ml. Cells grown as spheroids were more dense than the monolayer cells and were recovered mainly at 1.081. Solid-tumor cells, separated under the same conditions, banded at 1.080. Narrowing the range of the Ficoll gradient failed to resolve more than one band of cells in the solid-tumor separation. This provides evidence that the density of cells obtained from the spheroids is greater than that of the monolayer cells but agrees well with the density of the solid-tumor cells. Ficoll was demonstrated to be nontoxic to the cells, and plating efficiency assays showed similar cell viabilities between noncentrifuged and centrifuged cells. The plating efficiency of the peak fraction of exponential cells after centrifugation was 68%, and that of plateau-phase cells was 50%. Corresponding figures for the multicell spheroid and solid-tumor cells were 62 and 28%, respectively. The recovery of cells after centrifugation in the Ficoll gradients ranged from 62 to 83%. The effects of cell load and centrifugation time on the density distributions of the EMT6 cells were also investigated.
Forty patients with advanced solid tumors of diverse primary sites received a combination of cyclophosphamide (1 gm/m2), cytosine arabinoside (300 mg/m2), and methotrexate (80 mg/m2) given intermittently at 2-3-week intervals. Eight of the 40 patients received citrovorum factor rescue. The major limitation of therapy was suppression of bone marrow elements. Only minimal nonhematologic toxicity was encountered. Granulocytes appeared the most sensitive. The first course of treatment produced median nadir granulocyte and platelet counts of 1200 and 100,000 cells/mm3 respectively. Subsequent courses were tolerated with no evidence of increasing myelosuppression. Objective antitumor responses were noted in five of 16 patients with lung cancer and in eight of 14 women with breast cancer with a median duration of 8 months.
Nineteen patients with various solid tumors were treated with Corynebacterium parvum for 10 consecutive days at doses ranging from 0.5 to 6 mg/m2. Major toxic effects included rigors and cyanosis, hypertension, headache, nausea, and vomiting. Toxicity was maximal during the first 3 days of treatment and decreased or even disappeared when, on subsequent days, increasing doses of the vaccine were given. Objective tumor regressions were observed in four patients.
Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy in solid tumors is hindered by the immunosuppressive tumor microenvironment and by toxicities associated with viral-vector manufacturing. Non-viral gene delivery platforms have emerged as a potential alternative, though clinical evidence remains fragmented. METHODS: Following an a priori protocol registered on the Open Science Framework (OSF; https://doi.org/10.17605/OSF.IO/2TPQS) and adhering to JBI/PRISMA-ScR guidelines, a systematic search was conducted across four databases from inception through May 15, 2026. Patient-level data were extracted to describe cellular persistence and clinical outcomes across strictly non-viral delivery platforms. RESULTS: Four early-phase studies met the inclusion criteria, encompassing 28 heavily pretreated patients with metastatic solid tumors. Two non-viral platforms were identified: mRNA electroporation (n=19; intravenous in 13, intratumoral in 6) and the piggyBac transposon system (n=9). Across both mRNA routes, transient CAR-T persistence (<7 days) was observed, with no objective responses (ORR 0%), though disease stabilization yielded a disease control rate (DCR) of 53%; cross-route comparison is limited by differing distribution profiles. The piggyBac system showed longer persistence (~28 days) and a DCR of 78%, including the only documented objective response (ORR 11%). No Grade ≥3 cytokine release syndrome or neurotoxicity was reported in any of the 28 patients, and no tocilizumab or systemic corticosteroids were required. CONCLUSIONS: Within this limited early-phase evidence base, no severe toxicities attributable to non-viral platforms were reported, and the evidence identifies knowledge gaps warranting prospective investigation. mRNA platforms showed transient persistence and disease stabilization in 53% of patients. One partial response was documented with the piggyBac platform in a single patient; however, this outcome cannot be attributed to the delivery platform given simultaneous differences in target antigen, tumor histology, route of administration, and geographic setting. No firm conclusions regarding comparative platform performance can be drawn from this evidence base. SYSTEMATIC REVIEW REGISTRATION: https://doi.org/10.17605/OSF.IO/2TPQS, identifier OSF.IO/2TPQS.
Intratubular seminomas of the testis associated with solid tumors were studied by light and electron microscopy in order to obtain information about the earliest stage of emigration from the tubules and invasion of the interstitial space. Careful examination of numerous sections reveals that at this stage neoplastic cells protrude into evaginations of the tubule covered by basement membrance or directly invade that membrane. At the site of tumor cell emigration, the basement membrane is thickened and multilayered. Tumor cells devoid of basement membrane were found in the interstitium. Their transmigration through the basement membrane was never observed. Subsequent to the migration of seminoma cells the tubules are smaller in diameter and contain only Sertoli cells. From the observations described it is inferred that tumor cells in the interstitial tissue increase in number, form strands and lobules, and finally build up the solid tumor.
Piperazinedione was administered to 79 patients with solid tumors on an intermittent schedule with single doses of 1.5-36 mg/m2. Courses were usually repeated at 4-week intervals. Twenty-five patients with leukemia were treated at doses of 18-36 mg/m2 (occasionally for 2 successive days) every 1-4 weeks. Of 48 evaluable patients with malignant melanoma, three (6%) achieved partial remission and nine (20%) had stable disease. Eight of 17 (47%) patients with adenocarcinomas and one of two (50%) patients with lymphomas also had stable disease. Six of 14 (43%) patients with acute myelogenous leukemia showed hematologic improvement, as did one of 11 (9%) patients with blast cell crisis of chronic myelogenous leukemia. The principal toxic effect was myelosuppression, which occurred in 69% of the patients with solid tumors. Profound bone marrow aplasia occurred in 19% of the patients, resulting in six deaths (8%). Risk factors for marrow aplasia included extensive prior therapy, prior nitrosoureas, cumulative toxicity from piperazinedione, and abnormal liver function tests. The recommended doses for further studies are 9 mg/m2 for patients with risk factors for marrow aplasia, 12 mg/m2 for patients with prior therapy, 15 mg/m2 for previously untreated patients, and 24-36 mg/m2 for patients with acute leukemia.
Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that can enhance cellular immunotherapy. However, many genetic regulators of T cell performance in solid tumors may not be readily revealed in vitro. In vivo screening in tumor-bearing mice offers greater physiological relevance, but has historically been limited by low intratumoral T cell recovery. Here, we developed a new model system that achieves significantly higher human T cell recovery from tumors, enabling genome-wide in vivo screens with small numbers of mice. Tumor-infiltrating T cells in this model exhibit hallmarks of dysfunction compared to matched splenic T cells, creating an ideal context for screening for genetic modifiers of T cell activity in the tumor microenvironment. Using this platform, we performed two genome-wide CRISPR knockout screens to identify genes regulating T cell intratumoral abundance and effector function (e.g., IFN-γ production). The intratumoral abundance screen uncovered the P2RY8-Gα13 GPCR signaling pathway as a negative regulator of human T cell infiltration into tumors. The effector function screen identified GNAS (Gαs), a central signaling mediator downstream of multiple GPCRs that sense different suppressive ligands, as a key regulator of T cell dysfunction in tumors. Targeted GNAS knockout rendered T cells resistant to multiple suppressive cues and significantly improved therapeutic performance across diverse solid tumor models. Moreover, combinatorial knockout of P2RY8 (trafficking) and GNAS (effector function) further enhanced overall tumor control, demonstrating that genetic modifications targeting distinct T cell phenotypes can be combined to improve therapeutic potency. This flexible and scalable in vivo screening platform can be adapted to diverse tumor models and pooled CRISPR libraries, enabling future discovery of genetic strategies that equip T cell therapies to overcome barriers imposed by solid tumors.
The size and kinetics of the cell population of six advanced human solid tumors were analyzed following the continuous infusion of H3-TDR for a period of 6 to 21 days. By using the labelling indices of the cells in interphase and mitosis, and the rate of label incorporation, it was found the only 10 to 40% of the tumor cell population was replicating at any given time. Fifty-five percent to 85% of the remaining cell mass eventually entered into cycle at least once. Anywhere from 5% to 40% of the cell population remained arrested in G2 or G0 in individual cases during the period of observation. The significant size of the "resting" cell compartment is undoubtedly one explanation for the relative insensitivity of advanced adult solid tumors to current cell cycle-oriented therapeutic regimens.