Jonathan R. Sporn

Immunization with a tumor-cell-lysate-loaded autologous-antigen-presenting-cell-based vaccine in melanoma

Abstract The discoveries of human melanoma-associated antigens in molecular terms have renewed interest in peptide- or peptide- and antigen-presenting-cell (APC)-based cancer vaccines. Considering the limited scope of immunization using defined peptides, we have studied an alternative approach of specific immunization with tumor-lysate-loaded autologous APC (adherent peripheral mononuclear cells cultured in 1000 U granulocyte/macrophage-colony-stimulating factor for 14 days) as a surrogate vaccine. Seventeen patients (11 with active metastatic disease) were intradermally immunized with the vaccine in a phased dose escalation (105–107 cells/injection) monthly for 4 months. Thirteen patients completed all four immunizations showing no toxicity (3 patients had to be taken off study because of progressive disease and 1 patient went off study as a result of myocardial infarction due to multi-vessel coronary artery disease). None has shown any immediate or delayed toxicity attributable to the immunization and none has shown any evidence of autoimmunity. One patient showed a partial regression of a subcutaneous nodule. Thirteen patients are alive after 4+ months to 30+ months (17-month median survival for the group). Nine patients showed evidence of delayed-type hypersensitivity at the vaccine sites. Monitoring of biological response in conventional natural killer or cytolytic T lymphocyte assays with pre- and post-immune peripheral blood lymphocytes revealed no consistent differences. The vaccine-infiltrating lymphocytes (VIL) from nine specimens were adequately expanded following in vitro stimulation with the respective autologous-lysate-loaded APC for phenotypic and functional analyses. Five of the nine ex vivo expanded VIL were predominantly CD8+. Evidence of an antigen-specific CD8+ T cell response (cytotoxicity and/or tumor necrosis factor production) was detected in three of the five CD8+ VIL. These observations suggest that this type of vaccine is feasible, that it has biological activity, and that the approach may be improved through additional strategic manipulations.

Empiric chemotherapy in patients with carcinoma of unknown primary site.

Analysis of the results of chemotherapy in patients with carcinoma of unknown primary site is complicated by the small sizes of most treatment series and patient heterogeneity. Careful evaluation of clinical and pathologic information may identify patients with a relatively high likelihood of response to systemic therapy. This includes patients in whom immunohistochemical studies or electron microscopy, or both, suggest a likely tumor type responsive to systemic therapy, such as prostate cancer, lymphoma, or a neuroendocrine tumor. Clinical evaluation can also identify potentially responsive patients, particularly those with clinical features in common with the extragonadal germ cell tumor syndrome. For patients who do not fit into these more treatable categories, most combination chemotherapy programs have response rates of less than 30% and median survivals of less than one year. Randomized trials have not established any clearly superior chemotherapy program. Regimens containing both Adriamycin (doxorubicin) and mitomycin-C produce response rates of approximately 25% but are associated with the possibility of severe hematologic toxicity, and rarely a syndrome resembling the hemolytic-uremic syndrome. The choice between chemotherapy and supportive care only must be individualized, and the latter option is appropriate for many patients. More detailed clinical and pathologic analyses in conjunction with clinical trials, particularly employing newer diagnostic techniques, are vital to provide better prospective data from which to identify relevant clinical subsets that allow an estimate of an individual patients likelihood of response and the suitability of systemic chemotherapy.

Treatment of Advanced Pancreatic Adenocarcinoma with 5-FU, Leucovorin, Interferon-α-2b, and Cisplatin

Previous laboratory and clinical studies support the ability of interferon (IFN) to enhance the antitumor properties of chemotherapy agents, including cisplatin and 5-fluorouracil (5-FU). A phase I-II clinical trial was initiated to treat several tumor types with IFN-alpha-2b, cisplatin, 5-FU, and leucovorin (LV), given daily for 5 days of a 28-day cycle. Because of preliminary results, this was continued as a phase II trial in 18 patients with metastatic adenocarcinoma of the pancreas. Each treatment day consisted of IFN 5 million u/m2 s.c. (maximum, 10 million U), CDDP 20 mg/m2 i.v. over 1 h, LV 20 mg/m2 i.v.p., and 5-FU 250-275 mg/m2 i.v.p. All patients had measurable disease with no prior chemotherapy for metastatic disease, and all had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Six of the 16 patients evaluable for response had partial responses (PRs) (37.5%) with a median response duration of 4 months, and all responding patients survived > or = 8 months. Median survival of all 18 treated patients was 5 months. Severe gastrointestinal toxicity (nausea, diarrhea, or requirement for i.v. hydration) was common. Grade 4 hematologic toxicity was seen in six patients. The response rate observed is promising and supports the concept that IFN may potentiate the effects of standard chemotherapy agents. However, the toxicities observed with this dosage schedule were considerable and further studies are needed to develop a less toxic regimen.

Suppression of lymphokine-activated killer cell generation by tumor-infiltrating lymphocytes

A functional analysis of tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC) and malignant melanoma was performed. TILs were expanded in recombinant interleukin-2 (50 U/ml) in Iscoves medium. Phenotypic and functional (cytolytic vs regulatory) analyses were carried out with the fresh and expanded TIL populations after 4 weeks in culture. Only one TIL population from an RCC case (out of six cases studied) was CD8+ and demonstrated MHC class I-restricted tumor-specific cytotoxicity against the autologous RCC target. TIL populations from the other five cases became predominantly CD4+ and they neither killed the respective autologous tumor cells nor killed the NK-sensitive target K-562 cells. When studied for other functions, two CD4+ TIL populations were found to suppress the lymphokine-activated killer cell response by peripheral blood lymphocytes (PBL) in coculture. Of these two, a TIL population from an RCC case (MJ TIL) was used to study the cellular and molecular mechanisms of suppression. The MJ TIL synthesized a supernatant factor that blocked activation of resting PBL as measured by the induction of high-affinity IL-2 receptor (IL-2R) when stimulated by phytohemagglutinin but did not down-regulate the fully expressed IL-2R on activated T cells. The suppression of high-affinity IL-2R induction on T cells did not result from tumor necrosis factor-alpha and beta or from transforming growth factor-beta as these cytokines were not detected in the cell-free supernatant from the MJ TIL culture. The supernatant factor also suppressed IL-2-mediated enhancement of cytotoxicity by natural killer (NK) cells without demonstrating direct toxic effect on the NK cells. Thus, when TIL are used for adoptive immunocytotherapy, it may be useful to fully characterize them functionally, in vitro.

Practical recommendations for the management of adenocarcinoma of the pancreas

Pancreatic cancer is widely regarded by medical personnel and the lay public as one of the most dreaded of all diagnoses. Although in selected series of operable patients the chance of long term survival may reach 20%, most patients have unfavourable disease at the time of diagnosis, and for the entire group of newly diagnosed patients, 5-year survival is rare. This grim outlook results from a combination of factors, including an anatomical location which makes early detection by screening tests or by symptoms difficult, a high tendency for spread to regional lymphatics and the liver, a poor profile of sensitivity to chemotherapeutic agents and the poor medical condition of many patients at the time of diagnosis. These factors mean that it is particularly important that at the time of diagnosis these patients are carefully evaluated, and that they and their families are fully aware of the treatment options available to them and the associated potential risks and benefits.For localised cancers, surgical resection alone offers the potential for long term survival. The addition of postoperative radiation therapy (RT) predictably improves local control but has minimal impact on survival, which is primarily determined by the development of liver metastases. Randomised trial data support the use of combined fluorouracil (5-FU) chemotherapy and RT in patients who have undergone pancreatectomy and have negative margins, although the benefits are modest and the relevant randomised trials enrolled relatively small patient numbers. For patients with marginally resectable tumours, the feasibility has been demonstrated of using chemotherapy plus RT to reduce tumour size before resection, but it is unclear whether this approach will benefit a significant number of patients. Tumours which are unresectable because of local advancement (involvement of major vessels or regional nodes) can be treated with RT alone or in combination with chemotherapy, but survival past 2 years is uncommon.Patients with liver metastases have a poor prognosis. As part of a programme of supportive care, some of these patients may receive cytotoxic therapy, the goal of which is to relieve cancer-related symptoms such as pain from the primary tumour or metastatic sites, or weakness, nausea and anorexia which may be associated with liver metastases. Although the objective response rate of chemotherapy agents is low, in an individual patient they may produce an adequate response and acceptable toxicity so that the patient experiences overall improvement in symptoms. The mainstay of chemotherapy for pancreatic cancer, as with other gastrointestinal cancers, has been fluorouracil. However, recent clinical data have shown that gemcitabine produces similar results in terms of response rate and survival, with more acceptable toxicity, so that the quality of life was judged to be better than with fluorouracil.Pancreatic cancer provides a fertile ground for testing new, biologically based approaches to cancer therapy because of the limited success of currently available treatments.

Unusual presentation of a Merkel cell carcinoma

Merkel cell carcinoma (MCC) is an uncommon, potentially lethal, cutaneous tumor that mainly occurs in sun-exposed skin of the head and neck area of the elderly. We report a case of MCC presenting as a 2-mm crusted erosion on the nose of an elderly patient, the smallest MCC reported thus far in the literature. The optimal management of MCC has not been clearly established. In view of its high local recurrence rate, predilection to metastasis, and significant mortality, aggressive treatment has been advocated. Identification of this tumor at such a small size posed a management dilemma because of lack of prospective treatment data involving biologic markers of prognostic significance for MCC.

Concurrent 72-Hour Continuous Infusion of Etoposide and Cisplatin in Metastatic Breast Cancer

We conducted a multiinstitutional phase II clinical trial to determine the toxicity, response, and survival rate of concurrent 72-h continuous infusion of etoposide and cisplatin in patients with metastatic breast cancer. A total of 26 women were enrolled, 4 of whom received no prior chemotherapy for metastatic disease. All patients were evaluated for toxicity, response, and survival employing the National Cancer Institute (NCI) Common Toxicity Criteria and the Eastern Cooperative Oncology Group (ECOG) response criteria. A total of 84 cycles of therapy were administered, median 3 (range 1 to 6). Severe grade 3 and grade 4 neutropenia occurred in 22 cycles (26%), and there were only 11 episodes (11%) of similar grade thrombocytopenia. Nausea and vomiting were seen in one third of cycles. A single patient (4%) had a complete remission, and seven patients (27%) had partial remissions for an overall objective response rate of 31% (95% confidence interval, 13 to 49%). Three of four patients (75%) without prior therapy for metastatic disease had objective responses. Median survival was 7 months. This combination regimen is active in extensively treated patients with metastatic breast cancer. It is responsible to further investigate the role of etoposide-cisplatin combination chemotherapy as firstline therapy for patients with metastatic breast cancer.

Sustained response of refractory prolymphocytic leukemia to fludarabine.

A patient with de novo prolymphocytic leukemia who was refractory to chemotherapy and splenic radiation achieved a dramatic sustained response following 3 courses of therapy with fludarabine.

Reversible Granulocytopenia in Association with Riluzole Therapy

OBJECTIVE: To report a case of severe neutropenia developing in association with riluzole 200 mg/d. CASE SUMMARY: A 63-year-old woman with amyotrophic lateral sclerosis (ALS) presented with nausea, anorexia, and fever two weeks following inadvertent dose escalation of riluzole from 100 to 200 mg/d. Granulocytopenia was diagnosed and evaluation for a possible causative infectious process was negative; riluzole was considered a possible offender. Blood counts returned to normal with discontinuation of riluzole and administration of filgramstim. DISCUSSION: Riluzole is a glutamate release inhibitor used in the treatment of ALS, a devastating, progressive neurodegenerative disorder affecting motor neurons. A variety of adverse effects have been described with riluzole therapy, most commonly dizziness and gastrointestinal disorders. In this patient, multiple investigations failed to reveal an infectious cause or other drug-induced cause for the granulocytopenia. CONCLUSIONS: Granulocytopenia has been reported as an adverse effect of riluzole but is not a complication well known to clinicians, and there are no detailed reports published in the literature. In this patient, several lines of evidence raise the possibility of a causal relationship between riluzole and granulocytopenia.

ACUTE ADULT T-CELL LEUKEMIA/LYMPHOMA PRESENTING WITH FLORID CUTANEOUS DISEASE

Adult T‐cell leukemia/lymphoma (atll) is characterized by cutaneous disease, hypercalcemia, associated htlv‐i infection, and a fulminant course refractory to therapy. A patient with acute atll is described, and the natural history of atll is reviewed.