JITC Top Articles of 2017

Renee N. Donahue†, Lauren M. Lepone†, Italia Grenga, Caroline Jochems, Massimo Fantini, Ravi A. Madan, Christopher R. Heery, James L. Gulley and Jeffrey Schlom

Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells...

Matthew J. Reilley, Ann Bailey, Vivek Subbiah, Filip Janku, Aung Naing, Gerald Falchook, Daniel Karp, Sarina Piha-Paul, Apostolia Tsimberidou, Siqing Fu, JoAnn Lim, Stacie Bean, Allison Bass, Sandra Montez, Luis Vence, Padmanee Sharma, James Allison, Funda Meric-Bernstam and David S. Hong

Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer.

Patrick A. Ott, F. Stephen Hodi, Howard L. Kaufman, Jon M. Wigginton and Jedd D. Wolchok

Cancer immunotherapy and in particular monoclonal antibodies blocking the inhibitory programed cell death 1 pathway (PD-1/PD-L1) have made a significant impact on the treatment of cancer patients in recent years. However, despite the remarkable clinical efficacy of these agents in a number of malignancies, it has become clear that they are not sufficiently active for many patients. Initial evidence, for example with combined inhibition of PD-1 and CTLA-4 in melanoma and non-small cell lung cancer (NSCLC), has highlighted the potential to further enhance the clinical benefits of monotherapies by combining agents with synergistic mechanisms of action...

Patrick Danaher, Sarah Warren, Lucas Dennis, Leonard D’Amico, Andrew White, Mary L. Disis, Melissa A. Geller, Kunle Odunsi, Joseph Beechem and Steven P. Fling

Assays of the abundance of immune cell populations in the tumor microenvironment promise to inform immune oncology research and the choice of immunotherapy for individual patients. We propose to measure the intratumoral abundance of various immune cell populations with gene expression. In contrast to IHC and flow cytometry, gene expression assays yield high information content from a clinically practical workflow...

Irene Scarfò and Marcela V. Maus

Chimeric antigen receptor (CAR) T-cell therapy represents a revolutionary treatment for haematological malignancies (i.e. B-ALL). However, the success of this type of treatment has not yet been achieved in solid tumors. One hypothesis is that the immunosuppressive nature of the tumor microenvironment (TME) influences and affects the efficacy of adoptive immunotherapy...

Sacha Gnjatic, Vincenzo Bronte, Laura Rosa Brunet, Marcus O. Butler, Mary L. Disis, Jérôme Galon, Leif G. Hakansson, Brent A. Hanks, Vaios Karanikas, Samir N. Khleif, John M. Kirkwood, Lance D. Miller, Dolores J. Schendel, Isabelle Tanneau, Jon M. Wigginton and Lisa H. Butterfield

As cancer strikes, individuals vary not only in terms of factors that contribute to its occurrence and development, but as importantly, in their capacity to respond to treatment. While exciting new therapeutic options that mobilize the immune system against cancer have led to breakthroughs for a variety of malignancies, success is limited to a subset of patients. Pre-existing immunological features of both the host and the tumor may contribute to how patients will eventually fare with immunotherapy. A broad understanding of baseline immunity, both in the periphery and in the tumor microenvironment, is needed in order to fully realize the potential of cancer immunotherapy...

Puzanov†, A. Diab†, K. Abdallah, C. O. BinghamIII, C. Brogdon, R. Dadu, L. Hamad, S. Kim, M. E. Lacouture, N. R. LeBoeuf, D. Lenihan, C. Onofrei, V. Shannon, R. Sharma, A. W. Silk, D. Skondra, M. E. Suarez-Almazor, Y. Wang, K. Wiley, H. L. Kaufman†, M. S. Ernstoff† and on behalf of the Society for Immunotherapy of Cancer Toxicity Management Working Group

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs’ therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently...

Howard L. KaufmanEmail author, Robert H. I. Andtbacka, Frances A. Collichio, Michael Wolf, Zhongyun Zhao, Mark Shilkrut, Igor Puzanov and Merrick Ross

Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival...

Qiong Xue†, Emily Bettini†, Patrick Paczkowski, Colin Ng, Alaina Kaiser, Timothy McConnell, Olja Kodrasi, Máire F. Quigley, James Heath, Rong Fan, Sean Mackay, Mark E. Dudley, Sadik H. Kassim and Jing Zhou

It remains challenging to characterize the functional attributes of chimeric antigen receptor (CAR)-engineered T cell product targeting CD19 related to potency and immunotoxicity ex vivo, despite promising in vivo efficacy in patients with B cell malignancies...

Qiong Xue†, Emily Bettini†, Patrick Paczkowski, Colin Ng, Alaina Kaiser, Timothy McConnell, Olja Kodrasi, Máire F. Quigley, James Heath, Rong Fan, Sean Mackay, Mark E. Dudley, Sadik H. KasTomoko Freshwater, Anna Kondic, Malidi Ahamadi, Claire H. Li, Rik de Greef, Dinesh de Alwis and Julie A. Stoneim and Jing Zhou

Traditionally, most monoclonal antibodies (mAbs) have been dosed based on body weight because of perceived contribution of body size in pharmacokinetic variability. The same approach was used in the initial pembrolizumab studies; however, following availability of PK data, the need for weight-based dosing for pembrolizumab was reassessed...

James L. Gulley, Jay A. Berzofsky, Marcus O. Butler, Alessandra Cesano, Bernard A. Fox, Sacha Gnjatic, Sylvia Janetzki, Shyam Kalavar, Vaios Karanikas, Samir N. Khleif, Ilan Kirsch, Peter P. Lee, Cristina Maccalli, Holden Maecker, Jeffrey Schlom, Barbara Seliger, Janet Siebert, David F. Stroncek, Magdalena Thurin, Jianda Yuan and Lisa H. Butterfield

Kristen M. Hege, Emily K. Bergsland, George A. Fisher, John J. Nemunaitis, Robert S. Warren, James G. McArthur, Andy A. Lin, Jeffrey Schlom, Carl H. June and Stephen A. Sherwin

T cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.

Nick M. Durham, Nick Holoweckyj, Randall S. MacGill, Kelly McGlinchey, Ching Ching Leow and Scott H. Robbins

The expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations.

Michael A. Cannarile†, Martin Weisser†, Wolfgang Jacob, Anna-Maria Jegg, Carola H. Ries and Dominik Rüttinger

The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development...

Juan R. Cubillos-Ruiz, Eslam Mohamed and Paulo C. Rodriguez

Established tumors build a stressful and hostile microenvironment that blocks the development of protective innate and adaptive immune responses. Different subsets of immunoregulatory myeloid populations, including dendritic cells, myeloid-derived suppressor cells (MDSCs) and macrophages, accumulate in the stressed tumor milieu and represent a major impediment to the success of various forms of cancer immunotherapy...

Mohanad H. Nada, Hong Wang, Grefachew Workalemahu, Yoshimasa Tanaka and Craig T. Morita

Human γδ T cells expressing Vγ2Vδ2 T cell receptors monitor foreign- and self-prenyl pyrophosphate metabolites in isoprenoid biosynthesis to mediate immunity to microbes and tumors. Adoptive immunotherapy with Vγ2Vδ2 T cells has been used to treat cancer patients with partial and complete remissions. Most clinical trials and preclinical studies have used continuous zoledronate exposure to expand Vγ2Vδ2 cells where zoledronate is slowly diluted over the course of the culture...

Brian T. Maybruck, Lukas W. Pfannenstiel, Marcela Diaz-Montero and Brian R. Gastman

The suppressive nature of immune cells in the tumor microenvironment plays a major role in regulating anti-tumor immune responses. Our previous work demonstrated that a soluble factor from tumor cells is able to induce a suppressor phenotype (SP) in human CD8⁺ T cells typified by loss of CD27/CD28 expression and acquisition of a potent suppressor function. The present study hypothesized that the soluble mechanism that is inducing the SP in CD8⁺ T cells are tumor-derived exosomes (TDEs).

Richard Nuccitelli, Amanda McDaniel, Snjezana Anand, John Cha, Zachary Mallon, Jon Casey Berridge and Darrin Uecker

We have been developing a non-thermal, drug-free tumor therapy called Nano-Pulse Stimulation (NPS) that delivers ultrashort electric pulses to tumor cells which eliminates the tumor and inhibits secondary tumor growth. We hypothesized that the mechanism for inhibiting secondary tumor growth involves stimulating an adaptive immune response via an immunogenic form of apoptosis, commonly known as immunogenic cell death (ICD)...

Howard L. Kaufman, Michael B. Atkins, Adam P. Dicker, Heather S. Jim, Louis P. Garrison, Roy S. Herbst, William T. McGivney, Steven Silverstein, Jon M. Wigginton and Peter P. Yu

As healthcare costs continue to rise, there has been great interest in understanding and defining the value of current therapeutic strategies for the treatment of cancer. Cancer immunotherapy has emerged as a clinically beneficial alternative to conventional therapies for a variety of malignancies. Characterized by broad clinical activity, durable response rates, distinct side effects, and unique response kinetics, immune-based agents are vastly different compared with traditional cytotoxic or targeted therapies...

Dylan J. Martini, Aly-Khan A. Lalani, Dominick Bossé, John A. Steinharter, Lauren C. Harshman, F. Stephen Hodi, Patrick A. Ott and Toni K. Choueiri

Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor.