Allogeneic transplantation after immunotherapy for relapsed/refractory non-Hodgkin lymphoma: a comparison with a historical cohort.

BACKGROUND AIMS: New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody-drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor (CAR) T-cell therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. METHODS: We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving Allo-SCT after immunotherapy in the pre-CAR T-cell therapy era and compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. RESULTS: The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years, 59% versus 46%), overall survival (4 years, 77% versus 44%), non-relapse mortality (4 years, 19% versus 22%) and acute (6 months, 15% versus 21%) and chronic (4 years, 18% versus 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower after immunotherapy (4 years, 4% versus 14%), although significance was not reached. The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. CONCLUSIONS: Consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR T-cell therapy.

An Allogeneic Multiple Myeloma GM-CSF-Secreting Vaccine with Lenalidomide Induces Long-term Immunity and Durable Clinical Responses in Patients in Near Complete Remission.

PURPOSE: This proof-of-principle clinical trial evaluated whether an allogeneic multiple myeloma GM-CSF-secreting vaccine (MM-GVAX) in combination with lenalidomide could deepen the clinical response in patients with multiple myeloma in sustained near complete remission (nCR). PATIENTS AND METHODS: Fifteen patients on lenalidomide were treated with MM-GVAX and pneumococcal conjugate vaccine (PCV; Prevnar) at 1, 2, 3, and 6 months. RESULTS: Eight patients (53.3%) achieved a true CR. With a median follow-up of 5 years, the median progression-free survival had not been reached, and the median overall survival was 7.8 years from enrollment. MM-GVAX induced clonal T-cell expansion and measurable cytokine responses that persisted up to 7 years in all patients. At baseline, a higher minimal residual disease was predictive of early relapse. After vaccination, a lack of both CD27-DNAM1-CD8+ T cells and antigen-presenting cells was associated with disease progression. CONCLUSIONS: MM-GVAX, along with lenalidomide, effectively primed durable immunity and resulted in long-term disease control, as suggested by the reappearance of a detectable, fluctuating M-spike without meeting the criteria for clinical relapse. For patients in a nCR, MM-GVAX administration was safe and resulted in prolonged clinical responses.

Tumor dormancy as an alternative step in the development of chemoresistance and metastasis - clinical implications.

BACKGROUND: The ability of a tumor to become dormant in response to suboptimal conditions has recently been recognized as a key step in tumor progression. Tumor dormancy has been found to be implicated in several tumor types as the culprit of therapy resistance and metastasis development, the deadliest features of a cancer. Several lines of evidence indicate that the development of these traits may rely on the de-differentiation of committed tumor cells that regain stem-like properties during a dormant state. Presently, dormancy is classified into cell- and population-level, according to the preponderance of cellular mechanisms that keep tumor cells quiescent or to a balance between overall cell division and death, respectively. Cellular dormancy is characterized by autophagy, stress-tolerance signaling, microenvironmental cues and, of prime relevance, epigenetic modifications. It has been found that the epigenome alters during cellular quiescence, thus representing the driving force for short-term cancer progression. Population-level dormancy is characterized by processes that counteract proliferation, such as inappropriate blood supply and intense immune responses. The latter two mechanisms are not mutually exclusive and may affect tumor masses both simultaneously and subsequently. CONCLUSIONS: Overall, tumor dormancy may represent an additional step in the acquisition of cancer characteristics, and its comprehension may clarify both theoretical and practical aspects of cancer development. Clinically, only a deep understanding of dormancy may explain the course of tumor development in different patients, thus representing a process that may be targeted to prevent and/or treat advanced-stage cancers. That is especially the case for breast cancer, against which the mTOR inhibitor everolimus displays potent antitumor activity in patients with metastatic disease by impeding autophagy and tumor dormancy onset. Here we will also discuss other targeted therapies directed towards tumor dormancy onset, e.g. specific inhibitors of SFK and MEK, or aimed at keeping tumor cells dormant, e.g. prosaposin derivatives, that may shortly enter clinical assessment in breast, and possibly other cancer types.