Hematopoietic Stem cell Transplantation (HCT), challenges and current application in therapeutic paradigm.
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Hematopoietic Stem cell Transplantation (HCT), challenges and current application in therapeutic paradigm.

Contributed by

Dr Abdul Rashid Shah

Consultant Hematologist & Bone marrow transplant specialist 

Kuwait Cancer Control Center 

Linkedin Dr Abdul Rashid Shah


Hematopoietic stem cell transplantation also known as Bone Marrow Transplantation is established curative modality for range of hematological disorders both benign as well as malignant. Stem cells are multipotent and have capability of self-renewal and differentiation, first identified in Hematopoietic system and likely present in many other tissues. The major therapeutic uses are, Transplantation of Allogeneic stem cells to reconstitute hematopoiesis in patients with bone marrow failure, genetic diseases or in those who will benefit from intensive radio chemotherapy like malignant hematological disorders. The source of stem cells could either be Autologous or Allogeneic, from either Bone marrow or peripheral blood. When the first hematopoietic stem cell transplant (HCT) was performed six decades ago, it was used as a last-resort therapy in an attempt to deliver high doses of radiation, chemotherapy and stem cell infusion to patients with incurable malignancies. HCT has become a life- saving procedure for millions of patients since then. In the US alone, there were almost 14,000 Autologous-HCTs and more than 8,000 Allogeneic HCTs performed in 2015 and the number of HCTs is steadily increasing. The success of HCT has resulted from continuous advances in the field. The recent advances of greatest impact can be grouped into three major categories: 1) reduction of transplant-related morbidity and mortality, 2) expansion of donor options, and 3) reduction of post-transplant relapse. There has been a substantial reduction in mortality after Allo- HCT owing to a decrease in organ damage, better prophylaxis and treatment strategies for infectious complications and improved techniques for the prevention and management of graft versus host disease (GVHD), despite the increasing number of older patients with more comorbidities undergoing Allo-HCT in recent decades.


Hematopoietic stem cell transplantation involves administration of healthy hematopoietic stem cells in patients with dysfunctional or depleted bone marrow function either to destroy tumor cells or generate functional cells that can replace dysfunctional cells depending on the disease being treated. For both autologous and Allogeneic stem cell transplantation you need to collect stem cells from either patient (Autologous) or donor (Allogeneic) by a process called mobilization and collection and infusing these cells into the patient after his diseased bone marrow is ablated by high dose chemotherapy/irradiation, A process known as conditioning. This follows by recovery of bone marrow known as engraftment which takes two to three weeks from stem cell infusion depending on type of transplant. During this inpatient process, supportive treatment with blood products, fluids and electrolytes, various prophylactic agents as cytopenias make it vulnerable to infections are needed. After engraftment patients are monitored for Acute Graft versus host disease (aGvHD) which may involve skin, liver, GI tract, lungs and other organs. Sinusoidal Veno-occlusive disease (VOD) is a rare complication (5%) especially in Myelo-ablative Allogeneic transplantation.

A Donor for all HLA matching has been a requirement for Allo-HCT for decades. The transplant outcomes have ranged from poor to suboptimal, depending on the degree of mismatch, being substantially at greater risk for GVHD and infections owing to impaired immune reconstitution. Limited availability of suitable HLA-identical donors has been a significant barrier for Allo-HCT eligibility for decades. High-resolution donor-recipient HLA matching for HLA- A, -B, -C, and -DRB1 alleles was shown to be associated with improved survival after Allo-HCT from unrelated donors by minimizing complications related to HLA mismatch. More accurate HLA typing led to a decreased availably of HLA-matched donors for a significant number of patients needing Allo-HCT. Recent developments lead to exploration of other sources like Haplo-identical, Matched unrelated and cord blood with equal efficacy and cure rates. Disease relapse remains the main challenge for both Auto and Allo-HCT. According to Center for International Blood and Marrow Transplant Research data, primary disease is responsible for almost two-thirds of deaths after Auto-HCT. Relapse-related mortality is less common after Allo-HCT because of GVT activity and a higher risk of early non-relapse mortality, The relapse risk can be decreased by inducing deeper responses to anti-tumor therapy prior to HCT, by enhancing the cytotoxic potential of a conditioning regimen and by using maintenance therapy. In Allo-HCT recipients.

Future developments

Many challenges remain, particularly in minimizing disease relapse and the severity of GVHD. Further research is needed on how to enhance the ability of donor immune cells to eradicate malignant cells without significantly increasing GVHD. This will be possible with the development of novel adoptive immune cell and targeted therapies, recent identification of GVHD biomarkers, the development and clinical testing of biomarker- based scoring algorithms to permit risk-adapted therapy for acute GVHD. Recently, novel key targets and signaling pathways have been identified in the pathogenesis of chronic GVHD, including Bruton’s tyrosine kinase (BTK), Janus kinases (JAKs), spleen tyrosine kinase (SYK), and many others. These insights have led to clinical testing of the BTK inhibitor ibrutinib, several SYK inhibitors and JAK1/2 inhibitors, including ruxolitinib with very promising results in early studies. Changes in transplantation practices with less-toxic conditioning regimens have allowed many patients of more advanced ages to be considered for HCT, and currently no strict upper age limit exists for this procedure. However, more studies are needed to better define the most optimal donor and patient selection and conditioning regimens, particularly for elderly patients with comorbidities. 2. Cellular Therapy a paradigm shift and its future in Hematological cancer management: The number of cancer cell therapies has increased considerably over the last few years. There are several different types of cellular therapies, including Chimeric antigen receptor (CAR) T cells, multiple tumor-associated antigen specific T cells (TAA-T), Natural killer (NK)-based and T-cell therapies based on novel technologies like CRISPR. Amongst the different types of cell therapies in development, approximately 50% are CAR T-cell therapies for various hematological malignancies and solid tumors having cured cancers in some patients who failed chemotherapy.  


The development of CAR-T cells has been a decades-long journey from late 1980s to the Food and Drug Administration (FDA) approval of Tisagenlecleucel in 2017. The first CAR was reported in 1993, when Eschar et al successfully combined the cytotoxic potential of a T cell with the specific targeting of an antibody in a single gene transfer. The earliest clinical trials with first-generation CAR-T cells in solid cancers were disappointing. Optimization of the basic construct over time has crucially included the addition of costimulatory domains leading to improved T cell activation and survival, and the identification of favorable target antigens, most prominently CD19. These developments have led to positive clinical outcomes, including reports of cure in patients with B cell malignancies. Optimizing CAR-T cell design and delivery raises the hope of a cure for many more people with malignancies and heralds an exciting new era in cancer treatment. While researchers, physicians, patients, and investors are excited by such potential therapy, there are still several major hurdles to overcome. For the vast majority of patients with blood and almost all solid cancers, CAR-T cells are not yet proven to be effective, are too toxic, or are not available due to expense or geography.

Current therapeutic range of Cellular therapy:

Multiple Myeloma

B cell maturation antigen (BCMA) is expressed in nearly all cases of myeloma and is not present on hematopoietic stem cells or non hematological cells. Among small numbers of very heavily pretreated patients, overall response rates of over 80% have been reported. As there remain no curative chemotherapy options in myeloma despite recent progress, there is significant potential for CAR-T cells to disrupt the treatment landscape. Non cellular immunotherapies, such as antibody-drug conjugates and bispecific antibody therapies, seem to provide alternative and may prove to be less expensive.

Myeloid malignancies

The curative potential of Allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has established proof of T cell-mediated immunotherapy, but there are issues in extending this concept to the application of CAR-T cell therapy. There are several proposed strategies to overcome these obstacles, including (1) identification of AML-specific antigen pairings required for initiation and maintenance of leukemogenesis that can be exploited by combinatorial antigen targeting; (2) early termination of CAR-T cell activity once remission is achieved with suicide constructs or transient CAR expression techniques and (3) myeloablative CAR-T cell therapy followed by rescue allogeneic hematopoietic stem cell transplantation. Target antigens explored thus far in preclinical models include CD33, CD123, Lewis-Y, CD44v6, FLT3 receptor, CLL-1, and the folate receptor β.

B Cell malignancies

CD19 expressing blood cancers appear most conducive to CAR-T cell therapy. High levels of tumor expression of the target antigen, ease of physical access to tumor cells through the blood and lymphatics, and the tolerability of the on-target off-tumor effect of B cell aplasia make CD19 a unique target. However, <5% of all new cancer diagnoses are CD19 expressing malignancies targetable by licensed products. The innovative strategies developed in CD19 expressing diseases to abrogate antigen-negative relapse, improve efficacy of tumor killing, improve CAR-T cell persistence, and increase control of activity and toxicity, are in parallel being pursued in efforts to bring CAR-T cell therapies to bear against other diseases.

T cell malignancies

Developing effective CAR-T cells against T cell malignancies, for which chemotherapy is rarely curative, will be a huge challenge. Particular obstacles include contamination of the autologous CAR-T cell product by malignant T cells carrying the CAR, as well as unwanted CAR-T directed death of fellow CAR-T cells (fratricide) and of healthy T cells owing to shared target antigen. Among the proposed solutions are alternative cellular vehicles for the CAR, of which CAR-NK cells appear to be gaining most attraction in early phase clinical trials against both T cell malignancies and other cancers.

Solid tumors

While immune checkpoint inhibitors have established proof of activated T cell efficacy against solid cancers, outcomes with first, second and third-generation CAR-T cell products targeting single antigens have been very disappointing compared with blood cancers likely owing to: (1) CAR-T cells face difficulty gaining access to target cells sitting within poorly vascularized tumor masses, walled-off by inflammatory cells and connective tissues. (2) On gaining access, CAR-T cells face a hostile, hypoxic and anti-inflammatory tumor microenvironment, attenuating their potential cytotoxicity. (3) CAR-T cells that do manage to penetrate a solid tumor and retain cytotoxic potential, the lack of ideal single-antigen targets and specificity with commonality of antigens on tumor and counterpart and nonmalignant tissue.

Next-generation CAR-T cells

There have been a variety of innovations in the technical design of CAR-T cells, to improve efficacy and reduce toxicity in hematological malignancies and solid cancers.  On-target off-tumor effects can be minimized by adding gated circuits requiring both antigens to be present for CAR activation or not gated circuits which will activate in the presence of one antigen only. Targeting one antigen or another can eradicate multiple clones and reduce antigen-negative relapse by either infusing 2 separate populations of CAR-T cells, transducing 2 CARs into the same cell or by the novel tandem CAR, common combination being CD19 and CD22. 


It is evident that the future of cellular therapy is very bright for patients with hematological malignancies, as not only one, but multiple different strategies are under clinical investigation and show promising activity. CAR-based treatments remain at the center of cellular immunotherapy with new variations and adaptations being developed to tackle some of the associated toxicity and logistical hurdles seen with traditional CAR T-cell therapies.                  


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