New Immunotherapy for HSCT Recipients at Risk of Leukemia Relapse


A new T-cell immunotherapy is showing promise in preventing the risk of relapse of leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), and the results have led to the launch of a first-in-human clinical trial of the approach, which relies on engineered T-cell receptors (TCRs).

HSCT, which plays a key role in treating many types of leukemia, is generally effective in preventing relapse compared with use of chemotherapy alone. However, relapse still occurs in approximately one-third of patients who undergo the procedure, and only a small percentage of those patients survive. New therapies are therefore needed to prevent and treat relapse in patients who have undergone HSCT.

There is compelling evidence that potent selective anti-leukemic effects can be delivered by donor T cells specific for particular minor histocompatibility antigens. TCRs isolated from minor histocompatibility antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage post-HSCT leukemic relapse.

As described in the study published in Blood, the novel form of immunotherapy was developed by a team led by Marie Bleakley, MD, PhD, of Fred Hutchinson Cancer Research Center and the University of Washington in Seattle. The treatment is comprised of memory T cells transduced with a lentiviral vector encoding a transgene with several elements:

  • TCR targeting a leukemia-associated minor histocompatibility antigen, HA-1
  • A CD8 co-receptor that allows the TCR to function in CD4 helper T cells
  • A safety-switch/suicide gene that allows researchers to turn the T cells off in the event of excessive toxicity
  • A selection tag to enrich and track the cells

“The introduction of CD8 co-receptors into CD4 T cells has previously been studied in several labs, but as far as we know this is the first time it will be studied in a clinical trial,” Bleakley told MedPage Today. “One of the slightly surprising, but very positive, aspects of the study is that we were able to incorporate multiple desirable elements into the vector and successfully deliver them to the T cells, enabling the T cells to specifically kill human leukemia and also express the safety and feasibility features.”

The engineered T-cell immunotherapy differs from chimeric antigen receptor (CAR) T-cell therapies, she explained. TCR T-cell immunotherapy and CAR T-cell immunotherapy are both forms of genetically engineered T-cell immunotherapy, but they differ in that CAR T-cell immunotherapy employs synthetic receptors with an antibody-like binding element for antigen recognition. “To create TCR T-cell immunotherapy we transfer natural TCRs that are found in the blood or tissues from one individual to T cells belonging to other people.”

CAR T-cell therapy is highly effective for treating CD19+ B-lineage acute lymphoblastic leukemia (ALL) even in the post-HSCT setting, but novel T-cell immunotherapies are required for patients with other leukemia types. “An advantage of TCR T-cell immunotherapy is that it is not limited to the recognition of cell surface molecules,” Bleakley noted. “TCRs respond to small protein fragment ‘peptides’ that can be derived from proteins in the cells, or on the surface. This really opens up the options for targets, and can provide excellent specificity.”

This T-cell immunotherapy holds clinical promise for multiple types of leukemia, she continued: “It may be a new immunotherapy suitable for treating, and ultimately preventing, relapse of acute myeloid leukemia, B-lineage ALL, or T-lineage ALL, in patients with a specific genotype. HA-1 TCR T-cell immunotherapy is suitable for managing relapse only in the context of allogeneic HSCT because it requires a specific genetic difference between donors and recipients. However, the post-HSCT setting might provide some unique advantages in amplifying the effectiveness of the antigen-specific T-cell immunotherapy. Ultimately, we may incorporate the TCR T cells into the stem cell graft — that is, a highly engineered stem cell graft, augmented for a potent ‘graft-versus-leukemia’ effect.”

If the HA-1 TCR immunotherapy is successful in clinical trials, it will serve as a proof of principle for a class of leukemia-associated antigens. The introduction of a CD8 co-receptor into CD4 T cells — providing CD4 T cell function and help for HA-1-specific CD8s by allowing the class I restricted TCR to function effectively in CD4 T cells — has not been studied in clinical trials before, Bleakley said, adding that an upcoming clinical trial may provide the first proof of concept of CD8 co-receptors in TCR T-cell immunotherapy.

phase I clinical trial for both children and adults with ALL or acute myeloid leukemia who are relapsing or predicted to relapse after HSCT is scheduled to be conducted at Fred Hutchinson, and should be open to patient enrollment by early 2018, she said.

Practicing oncologists should be aware of the HA-1 TCR T-cell immunotherapy as a potential option for patients who are relapsing, or at risk of relapsing, after HSCT, Bleakley added: “Oncologists need to be aware of the increasing number of T-cell immunotherapy options, beyond CD19 CAR T cells, for patients with leukemia and other cancers. If they have patients in need, it is worth re-checking the current options.”

Child bone-marrow transplant ‘first’


First human trial of new bone-marrow transplant method.

Mohammed Ahmed
Mohammed started going to school in September

Doctors at London’s Great Ormond Street Hospital have carried out a pioneering bone-marrow transplant technique.

They say the method should help with donor shortages since it does not require a perfect cell match.

Mohammed Ahmed, who is nearly five years old, was among the first three children in the world to try out the new treatment.

He has severe combined immunodeficiency syndrome and had been waiting for a suitable donor for years.

Mohammed, who lives in Milton Keynes, was referred to Great Ormond Street Hospital when he was a year old.

“Start Quote

We waited for a full match but it did not come. By the grace of God, we took the decision to have the treatment”

Jamil Ahmed, Mohammed’s dad

His condition – a weak immune system – makes him more susceptible to infections than most, and a bone marrow transplant is the only known treatment.

While Mohammed was on the transplant waiting list, he became extremely sick with swine flu.

At that time, his doctors decided Mohammed’s only real hope was to have a mismatched bone-marrow transplant, with his father acting as the donor.

Mohammed’s dad, Jamil, agreed to give the experimental therapy a go.

Before giving his donation, Jamil was first vaccinated against swine flu so that his own bone-marrow cells would know how to fight the infection.

Mohammed’s doctors then modified these donated immune cells, called “T-cells”, in the lab to engineer a safety switch – a self-destruct message that could be activated if Mohammed’s body should start to reject them once transplanted.

Safety net

Rejection or graft-v-host disease is a serious complication of bone-marrow transplants, particularly where tissue matching between donor and recipient is not perfect, and is one of the most difficult challenges faced by patients and their doctors.

Mismatched transplants in children – where the donor is not a close match for the child – are usually depleted of T-cells to prevent graft-v-host disease, but this causes problems in terms of virus infections and leukaemia relapse.

Blood cells
White blood cells protect the body against infections

The safety switch gets round this – plenty of T-cells to be transfused and later killed off if problems do arise.

Thankfully, the transplant carried out in 2011 was a success – Mohammed’s doctors did not need to use the safety switch.

Although Mohammed still has to take a number of medicines to ward off future infections, his immune system is now in better shape.

Jamil said: “We waited for a full match but it did not come. By the grace of God, we took the decision to have the treatment.

“Now he is all right. Sometimes we forget what he has been through. We are just so grateful.”

He said Mohammed would still need close monitoring and regular health checks over the coming years, but his outlook was good.

Dr Waseem Qasim, ‎consultant in paediatric immunology at Great Ormond Street Hospital and lead author for the study, said the new approach should hopefully mean children who received a mismatched transplant could enjoy the same chance of success as those given a fully matched transplant.

“We think Mohammed is cured of his disorder. He should be able to lead a fairly normal life now.”

A full report about Mohammed’s therapy and the research by Great Ormond Street Hospital, King’s College London and the Institute of Child Health has just been published in PLoS One journal.

There are currently about 1,600 people in the UK waiting for a bone-marrow transplant and 37,000 worldwide.

Just 30% of people will find a matching donor from within their families.

Donations involve collecting blood from a vein or aspirating bone marrow from the pelvis using a needle and syringe.

Sequence-Based Discovery of Bradyrhizobium enterica in Cord Colitis Syndrome.


BACKGROUND

Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin.

METHODS

We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls.

RESULTS

DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease.

CONCLUSIONS

We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen.

Souirce: NEJM

 


Sequence-Based Discovery of Bradyrhizobium enterica in Cord Colitis Syndrome
BACKGROUND
Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin.
METHODS
We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls.
RESULTS
DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease.
CONCLUSIONS
We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen.
Source: NEJM

 

ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death


BACKGROUND

No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation.

METHODS

We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation.

RESULTS

Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen.

CONCLUSIONS

ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation.

Source: NEJM

 

Bone Marrow Transplantation (BMT) in Myelodysplastic Syndromes: To BMT or Not to BMT—That Is the Question.


Those who treat patients with myelodysplastic syndromes (MDS) have been forced to become comfortable with a rather uncomfortable truth. MDS is a bone marrow failure syndrome that represents the most commonly diagnosed myeloid malignancy and predominantly affects older adults, with a median age at diagnosis of 71 years.1,2 The only cure for MDS is hematopoietic stem-cell transplantation (HSCT). For a variety of reasons, including patient comorbidities, availability of related or matched donors, related donor comorbidities, physician and patient preference, and treatment-related adverse events, transplantation is only considered in approximately 5% of patients with MDS.2 Thus, even when we offer disease-modifying therapies such as azacitidine, decitabine, and lenalidomide, we are ultimately palliating 95% of our patients.36Despite this, patients often perceive these drugs to have curative potential in this setting, but cure is unfortunately not possible with these agents.7

How do we change this paradigm? Although some factors, such as patient comorbidities and availability of donors, are largely immutable, others factors have improved, making HSCT more appealing. One such advance is reduced-intensity conditioning transplantation, which greatly reduces the toxicity of the preparative regimen without compromising efficacy, and in so doing has raised the age for potentially eligible transplantation candidates into the eighth decade.8 Another modifiable area is in identifying patients for whom the risk-benefit analysis for transplantation is more favorable compared with managing the disease with palliative intent. This, in turn, could affect patient and physician preferences.

In the article that accompanies this editorial, Koreth et al9 report on a Markov decision analysis exploring the role of reduced-intensity allogeneic HSCT in older patients with MDS. This statistical technique relies on assumptions, which themselves are based on best estimates of outcome given in previously published studies, to play out scenarios of what would happen in real life to a given patient if he or she decided to undergo HSCT early, at or near diagnosis, or instead to pursue supportive care, growth factor, or disease-modifying therapy. Although this approach is not perfect, it does allow for sensitivity analyses in which assumptions can be changed to see if the same conclusion holds, and it is the best substitute available in the absence of prospective, randomized studies. This is also not the first time some of these investigators have tackled this question, or this methodology. In 2004, Cutler et al10 published a decision analysis of patients with MDS treated with myeloablative conditioning transplantation. Given this conditioning regimen, patients were younger (with a median age of 40.4 years), and given the timing at which this analysis was conducted, a paucity of individual patient data were available to appropriately reflect nontransplantation treatment approaches. So, although the results of the study by Cutler et al make clinical sense, namely, that early transplantation provides maximal quality-adjusted survival in higher-risk patients with MDS (those falling into intermediate-2 and high-risk categories of the International Prognostic Scoring System [IPSS]), these conclusions have always given treating doctors pause because the participants did not reflect the full spectrum of patients with MDS who are seen in everyday clinical practice.

The analysis by Koreth et al9 addresses these shortcomings. Now, given the nonmyeloablative preparative regimen, the median age of the 132 patients undergoing transplantation gleaned from the Center for International Blood and Marrow Transplant Research, Dana-Farber Cancer Institute, and Fred Hutchinson Cancer Research Center data sets is 64 years—closer to what we see in clinic. Patients who did not undergo transplantation included 132 with lower-risk disease (IPSS low and intermediate-1) receiving best supportive care; 91 anemic or transfusion-dependent patients receiving erythropoiesis-stimulating agents; and 164 higher-risk patients with MDS receiving azacitidine or decitabine. Patients being treated with lenalidomide, immunosuppressive approaches, or drug combinations were not included. Primary end points of the model were life expectancy (LE) and quality-adjusted life expectancy, an end point adjusted for quality of life, the values of which were derived from studies in which patients may not reflect those included in the current analysis. The authors tried to keep the assumptions used in an already complicated model to a minimum, and in so doing ignored some real-life scenarios, such as a patient initially in the nontransplantation arm deciding at a later time to undergo transplantation. That being said, the results suggest that for lower-risk patients with MDS, median LE for those avoiding HSCT was approximately double that of those undergoing HSCT, at 77 versus 38 months. For higher-risk patients, a more modest advantage was seen for early HSCT, with a median LE of 36 months, versus 28 months for nontransplantation approaches. Interestingly, in the Kaplan-Meier survival curve, that advantage starts to become apparent only after 40 months of follow-up, when the therapy-related adverse effects of HSCT have been realized.

In a separate article accompanying this editorial, Voso et al11 report on a validation of the revised IPSS (IPSS-R) in a cohort of 380 patients with MDS who were registered in the Gruppo Romano Mielodisplasie and diagnosed over a 10-year period. The IPSS-R was developed to improve on what have been regarded as shortcomings of the classic IPSS, including both an underrepresentation and relative discounting of the importance of cytogenetic abnormalities, sensitivity to degrees of cytopenias, and weight given to blast percentage.12,13 The authors found that the IPSS-R was able to predict leukemia-free and overall survival in their population and that it was able to make these predictions better than the classic IPSS and WHO prognostic scoring system. This is not in itself novel—the initial publication of the IPSS-R included validation in a separate cohort from the Medical University of Vienna and demonstrated improved discriminatory capacity compared with the classic IPSS. However, this article does advance the field in showing the ability of the IPSS-R to retain its predictive abilities in a small cohort of patients treated with disease-modifying agents—a group not included in the development or validation of the IPSS-R previously. It remains to be seen whether the IPSS-R remains robust in larger cohorts of treated patients, or whether additional revisions to the IPSS-R may be required for treated patients as a group or for specific therapies. This task (determining whether further revisions are needed) is already being initiated by the International Working Group.

How can we apply these two publications to the next patient with an MDS who walks into clinic? In practice, the IPSS and IPSS-R are used both to predict survival and to help determine therapeutic approach. A patient falling into lower-risk categories is much more likely to be treated with erythropoiesis-stimulating agents, lenalidomide, immunosuppressants, or supportive care, whereas a higher-risk patient should be considered for hypomethylating agents or HSCT. The article by Voso et al11 helps refine our definition of lower and higher risk and starts to substantiate it in treated patients, whereas the article by Koreth et al9 adds further support to pursuing HSCT in higher-risk patients at presentation—as defined by the IPSS, not the IPSS-R. What remains are questions regarding the best approach for patients in the IPSS-R intermediate-risk category, who are neither lower nor higher risk, and the need to validate these approaches prospectively, given that our best data for most MDS management principles remain circumstantial. Unfortunately, there’s the rub.

Source: JCO

 

Hans-Peter Kiem genetically manipulates stem cells to treat HIV, genetic diseases and cancers.


Fred Hutch oncologist, stem cell and gene therapy researcher

Imagine if we could treat deadly diseases by generating healthier versions of the very building blocks of our bodies—blood stem cells. That’s the vision of Dr. Hans-Peter Kiem, whose Hutchinson Center laboratory is working to make such therapies a reality.

“Not long ago, this was science fiction,” he said.

Kiem’s cutting edge research reflects his longstanding interest in blood stem cell transplantation, now one of the standard treatments for many blood cancers, in which the patient receives an infusion of blood stem cells, either from a donor or from the patient’s own multiplied cells. The idea is that the new stem cells will grow into disease-free blood cells—a concept that Kiem’s research takes a step further.

“Stem cells can do everything,” said Kiem, who first came to the Hutchinson Center as a fellow in 1992 and joined the faculty five years later. “If we can correct defective stem cells, we can cure diseases.”

Kiem and his colleagues investigate how stem cells can be extracted from sick patients, manipulated at a genetic level and then delivered back to them to treat a range of diseases, from infections like HIV to genetic diseases to aggressive cancers.

One ongoing research effort confronts a major challenge in cancer treatment: Patients can receive only so much chemotherapy at a time, or else their blood cell counts may drop to a level that invites infections, anemia, excessive bleeding and other serious health complications. In such a scenario, the patient must stop receiving chemotherapy until the cell counts recover to healthy levels—but meanwhile, the cancer can worsen.

Kiem’s lab has developed a way to extract a patient’s blood stem cells and insert a special “resistance” gene that is designed to protect the cells from damage by common chemotherapy drugs such as temozolomide and BCNU. An infusion of these enhanced cells could give new hope to patients with the most aggressive form of brain cancer—glioblastoma—which is very difficult to treat. A small study for glioblastoma patients that Kiem started in fall 2009 is showing promising initial results and continuing to expand.

Kiem is also planning a study of patients with AIDS and lymphoma, who would receive blood stem cells with two inserted genes: one that counteracts the HIV infection and one that protects the patient from chemotherapy’s effects.

More recently Kiem has extended his work to derive blood stem cells from a new class of stem cells called induced pluripotent stem cells. What makes pluripotent stem cells promising for new treatments is that they can be derived from readily accessible adult tissues, such as skin cells, and can mature into many other types of tissues and cells, including blood stem cells. These blood stem cells could in turn be expanded and used for blood stem cell transplantations, offering a new treatment option for patients with defective marrow or immune function.

Kiem’s groundbreaking work led to his selection in 2009 as the recipient of the first José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research. The award is named for internationally known tenor and leukemia survivor Carreras and Thomas, who developed bone marrow transplantation.

Don Thomas was pursuing something that was at that time viewed as very difficult,” Kiem said. “It’s a bit of the same thing right now for gene therapy in stem cells. I hope that in 10 or 20 years it will be like what Don has achieved.”

Source: Fred Hutchinson Cancer Research Center

 

 

 

Fred Hutchinson transplant program pioneers treatment options for minority patients struggling to find a donor match.


Patients from ethnic minority and mixed-racial backgrounds are less likely to receive a lifesaving bone marrow transplant than Caucasian patients with the same disease due to lack of matching donors, according to the National Marrow Donor Program (NMDP).

The likelihood of a patient finding a bone marrow donor match is highly dependent on genetic similarities between the patient and donor. Seventy percent of patients in need of a transplant do not have a matching donor in their family, according to Be The Match, operated by the NMDP. These patients must instead turn to a donor registry or alternative methods for treatment. Unfortunately, few minority patients have either a matched family member or an identified matched unrelated donor. This is due to complex genetic factors and low donor-registration numbers.

Seattle Cancer Care Alliance (SCCA) is working with Fred Hutchinson Cancer Research Center to pioneer new lifesaving transplant procedures to reduce the need for matching bone marrow donors by providing bone marrow or blood stem cell transplants to patients who would not typically be candidates due to lack of a matching donor.

“The striking difference in donation levels echoes the need to raise awareness of the bone marrow and umbilical cord blood donation registries, while continuing the development of transplant programs that expand the availability of these life-saving treatment to more people,” said SCCA’s Colleen Delaney, M.D., MSc, director of the Cord Blood Transplant Program and associate member of the Clinical Research Division at Fred Hutch. “Thanks to innovative treatments developed at Fred Hutch and available today through the SCCA Transplant Program, nearly all patients in need of a bone marrow or blood stem cell transplant will be able to identify a donor. Our goal is to make sure every patient who needs a blood stem cell transplant will get one with survival rates that are equivalent to conventional unrelated donors.”

Delaney is a renowned expert in the development of novel methods to grow cord blood stem cells in the laboratory and has pioneered steps toward reducing the risk of life-threatening infections in patients who receive a cord blood transplant.

Cord blood is unique from other sources of stem cells for bone marrow transplants. This leftover blood in the umbilical cord, which is collected immediately after birth without harm to the infant or mother, contains immune cells that are protected from foreign invaders such as bacteria and viruses. Due to this protection, these “naive” immune cells do not perceive a patient’s unmatched stem cells as a threat. This means cord blood transplants do not require a near identical genetic match between donor and patient for successful treatment. Most cord blood transplants involve a genetically mismatched donor and patient.

While cord blood transplant recipients have been at high risk for early post-transplant complications due to the low number of cells available in a single cord blood unit, Delaney’s innovative methods for expanding the number of cord blood cells per unit prior to transplant have been able to reduce such risks.

Jessie Quinn, a patient of half-Caucasian and half-African American ancestry, knows first-hand the lifesaving promise of expanded cord blood cells method. A survivor of acute myelogenous leukemia (AML), Quinn was the first patient to participate in an SCCA clinical study led by Delaney using her novel approach with expanded cord blood cells. Quinn credits her survival to the Fred Hutchinson Transplant Program at SCCA and her doctors’ dedication to developing innovative options for patients unable to find a donor match.

The Fred Hutchinson Transplant Program at SCCA also provides successful haploidentical transplants for patients unable to find a relative who is a perfect match. Led by Paul O’Donnell, M.D., Ph.D., medical director of SCCA’s Adult Transplant Service and researcher in the Clinical Research Division at Fred Hutch, haploidentical transplants are performed when a patient’s relative offers a partial donor match. Through advances in drug therapies, physicians are able to control the adverse immune system responses that previously prevented these partially matched relatives from serving as donors. Haploidentical transplants are especially beneficial for pediatric patients using their parents or siblings as donors.

“Patients should not give up hope if they run into difficulties finding a donor,” O’Donnell said. “At SCCA, we are committed to turning cancer patients into cancer survivors. Sometimes that means exploring alternative options and looking into clinical trials to help our patients conquer cancer. The Fred Hutchinson Transplant Program at SCCA offers patients additional treatment plans when they often believe they are out of options.”

O’Donnell is currently leading a multi-center, randomized clinical trial to determine the effectiveness of double unrelated umbilical cord blood transplants versus haploidentical related bone marrow transplants in people with leukemia or lymphoma. He is actively recruiting patients. A multi-center randomized Phase II study led by Delaney is also currently recruiting patients to evaluate the clinical efficacy of giving study participants umbilical cord blood cells that have been expanded in the laboratory to increase the number of cells available for the transplant.

SCCA has been at the forefront of revolutionizing transplant treatment options since the clinical use of bone marrow and stem cell transplantation was first developed at the Fred Hutch more than 40 years ago. One of its founders, E. Donnall Thomas, M.D., won the 1990 Nobel Prize in physiology or medicine for this groundbreaking work. As a result of Thomas’ innovation, the world’s millionth blood stem cell transplant procedure took place in January of this year. To date, SCCA’s doctors have performed more than 14,000 bone marrow transplants and the clinic consistently ranks among the country’s top transplant centers in one-year patient survival rates.

Fred Hutch continues to lead transplant research and has pioneered the use of transplants to treat autoimmune disorders and other, non-cancerous diseases. By developing “mini-transplants” that use minimal doses of radiation resulting in reduce side effects, older patients who were not previously eligible for transplants now have an additional treatment option.

For more information about the Fred Hutchinson Transplant Program at SCCA, please visit:http://www.seattlecca.org/diseases/bone-marrow-transplant-overview.cfm.

Source: Fred Hutchinson Cancer Research Center

 

 

A cure for HIV: where we’ve been, and where we’re headed.


2013 marks the 30th anniversary of the discovery of HIV.130 Years of HIV Science: Imagine the Future, a meeting at the Pasteur Institute in Paris, France, in May, 2013, sought to celebrate successes in countering the HIV/AIDS epidemic and to map out the challenges ahead.

The successes have been spectacular. Antiretroviral therapy (ART) has transformed what was once a death sentence into a chronic manageable disease. ART not only prolongs life, but dramatically reduces HIV transmission. ART is now available to 8 million people living with HIV in low-income and middle-income countries.2 In 2011, the numbers of new infections declined by 50% in 25 countries—many in Africa, which has the largest burden of disease.2 These advances are a result of transformative science, advocacy, political commitment, and effective partnerships with affected communities.

However, substantial challenges exist to maintain access to and funding for lifelong ART to the more than 34 million people with HIV. The costs of delivering ART are overwhelming many organisations and public health systems; we must continue to search for alternatives to lifelong treatment to benefit patients at manageable costs to health systems. With that aim, the International AIDS Society (IAS) global scientific strategy,3 Towards An HIV Cure, was launched in 2012.

Reports of both sterilising cure (elimination of all HIV-infected cells) and functional cure (long-term control of HIV replication after ART) have raised hope that a cure for HIV can be achieved—at least in a subset of individuals. The first and only reported case of sterilising cure was Timothy Brown, the Berlin patient, an HIV-infected man given a bone marrow transplant for acute myeloid leukaemia. The donor was naturally resistant to HIV because of a mutation in the CCR5 gene—a critical protein required by HIV to enter and infect cells.4 Brown stopped ART very soon after transplantation and he remains free of HIV after 6 years.

The Mississippi baby seems to be the first case of functional cure of an infant due to ART given 30 h after birth.5 After 18 months, ART was stopped and the infant continues to have undetectable HIV in blood or tissue. Deborah Persaud and colleagues, who studied the baby, don’t yet fully understand what cured the infant. Very early treatment might prevent formation of latent reservoirs for HIV, at least in an infant with an immature immune system. Careful follow up and further studies will be needed to see if this approach can be replicated in more infants, and then on a larger scale.

In the VISCONTI cohort,6 14 patients in France have maintained control of their HIV infection for a median of 7·5 years after ART interruption.6 These so-called post-treatment controllers were diagnosed and treated with ART during primary HIV infection (on average within 10 weeks after infection), for a median of 3 years before discontinuation. Patients in this cohort do not have the same distinct immunological profile seen in elite controllers, who naturally control HIV in the absence of ART.6 The VISCONTI study potentially shows the benefits of early ART on the size of the reservoir. Further studies of reservoir size in patients who initiate ART in chronic infection but with high CD4 counts are to be presented at IAS 2013, Kuala Lumpur, Malaysia (Hocqueloux, WEAB0102; Chéret, WEAB0101).

Bone marrow transplantation, from a donor without a mutation in CCR5, might substantially reduce or even eliminate the HIV reservoir. Two patients with lymphoma from Boston (MA, USA) were given chemotherapy, radiotherapy, and stem cell transplantation while on continuous ART. Several years after transplantation, HIV DNA had disappeared from both patients’ blood and tissues.7 An update on the Boston patients is anticipated at IAS 2013 (Henrich, WELBA05).

The other approach to tackle HIV persistence in patients taking ART is to lure HIV out of its hiding place in resting T cells. Activating latent virus might lead to death of the cell or make the virus ready for immune-mediated clearance. A range of licensed drugs that modify gene expression, including viral gene expression, are in clinical trials in HIV-infected patients on ART. Two studies89 have reported that HIV latency can be activated with the histone deacetylase inhibitor vorinostat.

There are now 15 HIV-cure-related trials being done worldwide.3 Clinical trials include investigations of increasingly potent histone deacetylase inhibitors, and of gene therapy to eliminate the CCR5 receptor from patient-derived cells.

HIV-cure-related trials raise many complex issues. Giving potentially toxic interventions to patients doing very well on ART needs careful assessment. At this early phase of research, participants will be unlikely to derive any direct benefits. Understanding risk—benefit, ethical issues, and the expectations and perspectives of the community will all be discussed and debated at IAS 2013 and the preceding IAS workshop, Towards an HIV Cure.

Developments towards a cure for HIV are exciting—for scientists, for clinicians, and most importantly, for patients. But we need to be realistic. Finding a cure will be a long and tough road, and will take many more years to achieve. We are at the very beginning, although many now believe that it might be possible to find a cure, at least for a small proportion of infected people.

We need to take inspiration from the many people who have delivered so much in the past 30 years, and continue to imagine, continue to innovate, and continue to work together towards an HIV cure—for everyone.

Source: Lancet

 

Autologous and Allogeneic Stem-Cell Transplantation for Transformed Follicular Lymphoma: A Report of the Canadian Blood and Marrow Transplant Group.


Abstract

Purpose To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone.

Patients and Methods This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation.

Results One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio [HR], 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT.

Conclusion Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.

Source: JCO