We selectively expand the T cells in the laboratory, conferring them with the ability to kill tumor cells. Because they are not ‘engineered,’ they are not as complicated to make, and they have proven to be both safe and associated with clinical benefit.— Ann M. Leen, PhD
Adoptive T-cell therapy using “non-engineered” T cells has been showing activity in hematologic malignancies, according to a presentation by Ann M. Leen, PhD, at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium.1 Dr. Leen is an immunologist and works at the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston. She is also a cofounder and equity holder of Marker Therapeutics.
The strategy has been used on 36 heavily pretreated patients with lymphoma or multiple myeloma, the majority of whom have attained complete or partial responses, many of them quite durable. In addition, the safety profile has been excellent, Dr. Leen reported. Clinical trials of the therapy are ongoing in lymphoma, multiple myeloma, acute myeloid leukemia, acute lymphoblastic leukemia, and solid tumors.
‘Natural’ Selection and Expansion
Adoptive T-cell therapy expands a patient’s own antigen-specific T-cell population. This is typically done through engineering that endows T cells with novel receptors and that enlists viral vectors to reintroduce the cells into the patient. Dr. Leen’s approach does not rely on cellular engineering and as such is more “natural,” she said. “We selectively expand the T cells in the laboratory, conferring them with the ability to kill tumor cells. Because they are not ‘engineered,’ they are not as complicated to make and have proven to be both safe and associated with clinical benefit. We are just taking the patient’s own cells and giving them back in slightly improved form.”
A major challenge in developing and implementing adoptive T-cell therapy is the fact that the vast majority of malignancies are heterogeneous, she said. “Targeting a single antigen is likely to be insufficient for producing a sustained antitumor benefit and may lead to immune escape. Our approach to the problem of tumor heterogeneity was to develop tumor-specific T-cell lines that target multiple tumor-associated antigens simultaneously…. And within those antigens, we want to target multiple different epitopes through major histocompatibility class I and II pathways, ie, CD4-positive and CD8-positive cells.”
Dr. Leen and her team use T cells with tumor specificity mediated via their native T-cell receptors. These cells are expanded from the patient’s peripheral blood using antigen-presenting cells (specifically, dendritic cells in this case). These cells are loaded with overlapping peptide libraries that span up to five tumor-expressed antigens, which selectively enriches for tumor-specific populations, she explained.
“As such, the cells are not genetically engineered, and since the T-cell products target multiple tumor-expressed antigens simultaneously, the risk of immune escape due to antigen loss is minimized,” she said.
The tumor-expressed antigens in the product were MAGE-A4, PRAME, survivin, NYESO1, and SSX2. They are also known as shared, or cancer/testis, antigens, which are protein antigens whose normal expression is restricted to adult testicular germ cells but which are aberrantly activated and expressed in various types of cancer.
Clinical Trial in Lymphoma
Their first-in-human study included 27 patients with Hodgkin lymphoma (n = 10), aggressive non-Hodgkin lymphoma (n = 15), or composite lymphoma (n = 2). Of these patients, 12 had active disease and 15 received the product after autologous or syngeneic stem cell transplant (without lymphodepletion), for which the infusion was considered adjuvant therapy. Three dose levels were evaluated, the lowest being 10 million cells. Patients received 2 infusions, 2 weeks apart. No adverse events were observed after infusion at any dose level, Dr. Leen reported.
The active disease group included a number of patient types, including patients in second or subsequent relapse; in first relapse for indolent lymphoma after first-line therapy for relapse; in first relapse if immunosuppressive chemotherapy was contraindicated; with primary refractory or persistent disease after first-line therapy; with multiple relapses but now in remission and with a high risk for relapse; and with lymphoma as a second or transformed malignancy.
“After we infused our cells, we saw that strong activity of the T cells was generated against the five target antigens in patient blood samples. And remarkably, we didn’t just see an increase in signal against the antigens we were targeting, but also against other nontargeted, tumor-expressed antigens indicating in vivo epitope spreading, which further amplified the benefit of our therapy,” Dr. Leen reported.
T-cell activity correlated with clinical benefit, in almost all of these heavily pretreated patients. Out of 12 patients with active disease, 5 had complete responses. Of these, 3 responses were ongoing for more than 2 years and 1 has persisted for more than 1 year. One complete responder died of pneumonia after 4 months in remission.
Three patients achieved stable disease, with one patient remaining stable for 1 year. Three patients had progressive disease as the best response, and several patients were yet to be assessed.
Among the 15 patients receiving infusions as adjuvant therapy, who were heavily pretreated prior to transplant, all 15 remain in remission at a median of 17 months after infusion.
Dr. Leen commented, “In the setting of lymphoma, we showed it’s feasible to generate T cells. They have proven safe, and we have seen evidence of tumor lysis, in vivo epitope spreading, and clinical benefit.”
Results in Myeloma
Based on these encouraging findings, the researchers next evaluated the multitargeted T-cell product in multiple myeloma, for which they have an ongoing phase I/II trial of 2 cohorts: patients who are infused at least 90 days after autologous stem cell transplant, and patients who receive the infusion within 90 days of transplant. The question is whether the immune reconstitution will be different between these groups.
Early results in nine heavily pretreated patients appear to mirror the efficacy seen in lymphoma, Dr. Leen reported. For example, one patient had experienced multiple relapses and received the T cells after a second transplant. Free lambda served as a tumor marker; its levels were indicative of significant disease activity prior to transplant, but they normalized after infusion. At the time of her second transplant, she demonstrated 20% clonal plasma cells, which dropped to < 1% approximately 2 months after infusion; another tumor marker, cyclin D1, also became negative. The patient had a complete response and remains in remission 12 months after infusion, she said.
“The clinical benefit correlated with an increase in tumor-specific T cells in the peripheral blood and, interestingly, also in the bone marrow,” she noted. Dominant expansion against MAGE-A4 correlated with the antigen-expression profile of the tumor. Only one multiple myeloma patient has not responded to the treatment.
“We think we can draw the same conclusions for myeloma as for lymphoma, and we are also seeing the therapeutic potential of this product in leukemia and the solid tumors,” Dr. Leen added. ■
Disclosure: Dr. Leen is cofounder of and equity holder in Marker Therapeutics.
1. Leen AM: Multi-tumor-associated antigen-specific T cells for therapy. 2017 ASCO-SITC Clinical Immuno-Oncology Symposium. Education Session. Presented February 23, 2017.