Human Immunodeficiency Virus (HIV) Infection and Cancer

Human immunodeficiency virus type 1 (HIV-1) infection confers an increased risk for the development of many cancers. Although the incidences of acquired immunodeficiency syndrome (AIDS)-defining malignancies have declined since the advent of antiretroviral therapy (ART), a number of non-AIDS–defining cancers appear more common in HIV-1–infected individuals relative to the general population. ART-treated HIV-1–infected subjects are also aging, leading to an increased cancer burden in these populations. However, longevity alone is not sufficient to explain these epidemiologic trends. A causative link between HIV-1–induced immune suppression and elevated cancer risk is well defined in certain malignancies; however, the direct role of HIV-1 replication products in oncogenesis remains unclear. Nevertheless, it is evident that cooperation between HIV-1 and co-infecting viruses in targeting immune compartments as well as nonimmune microenvironments can regulate both the development and progression of cancer. Treating cancer in HIV-1–infected patients remains challenging due to drug interactions, compounded side effects and intensified immunosuppression from chemotherapy and/or radiation. While survival of HIV-1–infected patients with certain cancers now rivals that of their uninfected counterparts, a better understanding of HIV-1–induced oncogenesis, viral mechanisms of immune perturbation, nonimmune microenvironmental abnormalities and outcomes of therapy will provide the basis for better diagnosis and management of cancer

CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success

Chimeric antigen receptor (CAR)-engineered T cells represent a breakthrough in personalized medicine. In this strategy, a patient's own T lymphocytes are genetically reprogrammed to encode a synthetic receptor that binds a tumor antigen, allowing T cells to recognize and kill antigen-expressing cancer cells. As a result of complete and durable responses in individuals who are refractory to standard of care therapy, CAR T cells directed against the CD19 protein have been granted United States Food and Drug Administration (FDA) approval as a therapy for treatment of pediatric and young adult acute lymphoblastic leukemia and diffuse large B cell lymphoma. Human trials of CAR T cells targeting CD19 or B cell maturation antigen in multiple myeloma have also reported early successes. However, a clear and consistently reproducible demonstration of the clinical efficacy of CAR T cells in the setting of solid tumors has not been reported to date. Here, we review the history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies. In addition, we summarize recent strategies and innovations that aim to augment the potency of CAR T cells in the face of multiple immunosuppressive barriers operative within the solid tumor microenvironment. Advances in the field of CAR T cell biology over the coming years in the areas of safety, reliability and efficacy against non-hematopoietic cancers will ultimately determine how transformative adoptive T cell therapy will be in the broader battle against cancer

Engineered T Cell Therapies from a Drug Development Viewpoint

Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With major players within the pharmaceutical industry joining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy; adverse effects (AEs); and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals. Keywords: Engineered T cell therapies, Chimeric antigen receptor, Drug development process, Biomarkers, CD19-specific chimeric antigen receptor, Anti-CD19 chimeric antigen receptor T cell

Decade-long Remissions of Leukemia Sustained by the Persistence of Activated CD4 CAR T Cells

The adoptive transfer of T cells reprogrammed to target tumor cells has demonstrated significant potential in various malignancies. However, little is known about the long-term memory potential and the clonal stability of the infused cells. Here, we studied the fate of CD19 redirected chimeric antigen receptor (CAR19) T-cells in two leukemia patients who achieved and sustained a complete remission almost a decade ago. CAR T cells were still detectable 9+ years post-infusion. Surprisingly, a prominent, highly activated CD4+ population developed in both subjects in the years post-infusion, dominating the CAR T cell population at the late time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by few clones. Single-cell profiling of CAR T-cells obtained 9 years post-infusion demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with strong evidence of ongoing functional activation and proliferation. Given data that CD19 directed CAR T with a CD28 signaling domain do not persist long term, our data provide important insight into the development of long-term anti-tumor responses necessary for sustained remission in leukemia following CAR T-cell therapy

CRISPR/Cas9-based genome editing in the era of CAR T cell immunotherapy

The advent of engineered T cells as a form of immunotherapy marks the beginning of a new era in medicine, providing a transformative way to combat complex diseases such as cancer. Following FDA approval of CAR T cells directed against the CD19 protein for the treatment of acute lymphoblastic leukemia and diffuse large B cell lymphoma, CAR T cells are poised to enter mainstream oncology. Despite this success, a number of patients are unable to receive this therapy due to inadequate T cell numbers or rapid disease progression. Furthermore, lack of response to CAR T cell treatment is due in some cases to intrinsic autologous T cell defects and/or the inability of these cells to function optimally in a strongly immunosuppressive tumor microenvironment. We describe recent efforts to overcome these limitations using CRISPR/Cas9 technology, with the goal of enhancing potency and increasing the availability of CAR-based therapies. We further discuss issues related to the efficiency/scalability of CRISPR/Cas9-mediated genome editing in CAR T cells and safety considerations. By combining the tools of synthetic biology such as CARs and CRISPR/Cas9, we have an unprecedented opportunity to optimally program T cells and improve adoptive immunotherapy for most, if not all future patients