HIV Has Role in CAR-T Therapy

Image: CHOP

Stephan Grupp MD, PhD

Recent news stories profiling a cancer patient whose last hope rests on treatment by injections of the virus that causes AIDS may have created some misconceptions regarding a new cancer immunotherapy. Essentially, HIV-derived lentivirus vectors used for gene modification represent just a small piece of this promising scientific breakthrough.¹

Researchers from the Perelman School of Medicine at the University of Pennsylvania published the latest report on chimeric antigen receptor (CAR) T-cell therapy for patients with advanced leukemia inThe New England Journal of Medicinerecently, and demonstrated its effectiveness against the aggressive malignancy.²

The study’s senior author, Stephan Grupp MD, PhD, professor of pediatrics in the Perelman School of Medicine and director of translational research in the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia, explained the true significance of CAR T-cell therapy. “The patients who participated in these trials had relapsed as many as 4 times, including 60% [of patients] whose cancers came back even after stem cell transplants. Their cancers were so aggressive they had no treatment options left. The durable responses we have observed with CTL019 [CAR T-cell] therapy are unprecedented.”

Out of 30 children and adults with relapsed acute lymphoblastic leukemia (ALL), complete remission was seen in 27 patients. At 6 months, the event-free survival rate was 67%, and overall survival was 78%. Compared with rates of remission for treatment using FDA-approved drugs for relapsed ALL (clofarabine, nelarabine, and liposomal-encapsulated vincristine), which are less than 25% and median duration of response 4 to 9 weeks, the results from CAR T-cell therapy are encouraging.

The CAR T-cell immunotherapy protocol calls for an infusion of autologous, genetically engineered T cells, transduced with chimeric antigen receptors using an HIV-derived lentivirus vector, which has become the source of erroneous reports regarding the procedure.

Image: Penn Medicine

Carl June, MD

Carl June, MD, professor of immunotherapy and director of translational research in the Abramson Cancer Center at the University of Pennsylvania, and a lead researcher on the study, explains, “It's a disabled virus, but it retains the one essential feature of HIV, which is the ability to insert new genes into cells.” The vectors are commonly used for long-term, stable in vitro and in vivo gene transfer.

The chimeric receptors expressed in the T cells include an anti-CD19 single-chain Fv domain along with intracellular T-cell signaling domains, a combination that effectively redirects the cytotoxic T lymphocytes to cells expressing CD19, found on the surface of most B cells. Also included in the chimera are signaling domains to improve cytokine secretion, T-cell expansion, and persistence.

Once T cell expansion is under way, most patients develop delayed cytokine release and macrophage activation, known as cytokine release syndrome (CRS), with symptoms of high fever, hypotension, delirium, and aphasia. As part of the mechanism of elimination of cancer cells, cytokine release cannot be entirely prevented; but rather, it indicates the treatment is working. The toxicities can be managed using interventions such as interleukin-6 receptor blockade. Serum C-reactive protein may indicate the severity of the CRS to help manage the condition.

The modular construction of the chimeric receptors allows for flexibility in choosing the target for the engineered T cells. June’s research team is testing the therapy in pancreatic cancer patients by swapping out the anti-CD19 antibody domain and replacing it with an antibody specific for a molecule on the surface of pancreatic cancer cells.

Novartis, seeing the potential to change the cancer therapy landscape by reprogramming a patient’s immune system, committed $20 million to build a research center devoted to immunotherapy on the University of Pennsylvania campus. Novartis acquired exclusive rights to the CAR-T cell used in this trial, renaming it CTL019. It received the US Food and Drug Administration’s Breakthrough Therapy designation earlier this year, the first personalized cellular therapy for the treatment of cancer to receive this classification.³

June explains, “Virtually any tumor should be targetable with these CAR-T cells, but the targets have to be on the surface of a cancer cell, and an antibody needs to be made that can bind to that surface target. There’s a lot of energy in the field now trying to identify new targets so that virtually any cancer could be treated.” He hopes to increase the reach of the personalized therapy. “We are working to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

References

1. Collman A. Doctors cure father, 30, of leukemia by injecting him with HIV in experimental trial. Daily Mail Online. November 13, 2014.http://www.dailymail.co.uk/news/article-2830879/Is-HIV-cure-cancer-Married-father-one-30-leukemia-free-doctors-injected-virus-causes-AIDS-experimental-trial.html. Accessed November 13, 2014.
2. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia.N Engl J Med. 2014 Oct 16; 371(16): 1507-1517.
3. University of Pennsylvania Health System. University of Pennsylvania's Personalized Cellular Therapy for Leukemia Receives FDA's Breakthrough Therapy Designation.http://www.uphs.upenn.edu/news/News_Releases/2014/07/ctl019/Accessed November 13, 2014.