Australian Doctor 14th July Issue 14JULY2023 issue | Page 39

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The antibody-drug conjugate brentuximab vedotin is directed at the CD30 molecule that is present on the cells in Hodgkin ’ s lymphoma and a specific subtype of T-cell lymphoma , the anaplastic T-cell lymphoma . 22 Brentuximab vedotin ’ s major toxicity is peripheral neuropathy , which is often reversed on cessation of therapy .

Polatuzumab vedotin is an antibody-drug conjugate targeting the CD79 molecule present in many patients with non-Hodgkin ’ s lymphomas , specifically those with DLBCL . 23 A pivotal upfront trial of this agent in combination with chemotherapy for DLBCL demonstrated a benefit over R-CHOP , though it is not yet funded in Australia .

ANTIBODIES THAT ACTIVATE T-CELLS TO TARGET CANCER CELLS T-cells are critical in the recognition and destruction of cancer cells , but cancers can evolve to escape this immune surveillance . Harnessing the power of T-cells has long been a goal of cancer immunotherapy .

Checkpoint inhibitors Tumour cells express surface molecules that bind to and inhibit the activity of T-cells ; 24 these signals are known as checkpoints and include PD-1 and CTLA-4 that bind to their respective ligands on the T-cell PD-L1 and B7 thus inhibiting that cell ’ s function . Antibodies that target these checkpoints (‘ checkpoint inhibitors ’) and thus reinstate T-cell activity against tumour cells are effective in a range of malignancies , including melanoma , lung cancer and Hodgkin ’ s lymphoma . 25

The dense inflammatory infiltrate that is present in Hodgkin ’ s lymphoma and genetic overexpression of the PD-1 molecule means it is very sensitive to PD-1 blockade . 25 The PD-1 inhibitor pembrolizumab is approved for relapsed disease , and this class of checkpoint inhibitors is being investigated in earlier lines of treatment .

The broad upregulation of the immune system mediated by the checkpoint inhibitors can , however , cause a range of toxicities ( immune-related adverse events ). 26 Overactivation can lead to a range of organ inflammation syndromes : pneumonitis presenting with cough and dyspnoea , colitis presenting with diarrhoea , and endocrine dysfunction including thyroiditis . Treatment of immune-related adverse events include cessation of the immunotherapy and immunosuppression with steroids .

Bispecific antibodies Bispecific antibodies are antibodies that are engineered to have domains that recognise two different molecules or ‘ epitopes ’ — these are typically a molecule on the surface of the cancer cell , and a molecule on T-cells ( typically CD3 ), which then draws T-cells to cancer cells and activates a response that leads to cancer cell death ( see figure 10 ). 27

Blinatumomab , which binds to CD3 on T-cells and to CD19 on neoplastic B-cells , was the first approved bispecific antibody for the treatment of B acute lymphoblastic leukaemia . It must be given as a continuous infusion over 28 days because of its short half-life . 28

A range of bispecific antibodies

Ed Uthman / CC BY / bit . ly / 3MZzPXs

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Figure 4 . PET scan . A sixty-three-year-old male patient diagnosed ( and proven by histopathology ) with hepatic non-Hodgkin ’ s lymphoma .

A . Axial contrast-enhanced CT ( CECT ) of the abdomen showing three hypodense non-enhancing hepatic focal lesions seen at segment VIII ( red arrows ) and peri hepatic peritoneal nodular thickening ( blue arrows ).

B . Axial PET / CT showing avid fluorodeoxyglucose ( FDG ) uptake of the three hepatic focal lesions seen at segment VIII ( red arrows ) and peri hepatic peritoneal nodular thickening ( blue arrows ) previously noted on CECT , with two additional FDG avid hepatic focal lesions seen at segment IV ( yellow arrows ) and right pleural nodular thickening underlying the pleural effusion ( green arrow ), not seen on CECT .

C . Axial CECT showing three hypodense non-enhancing hepatic focal lesions ; two of them seen at segment VIII ( long red arrows ) and one seen at segment VII ( short red arrow ) with peri hepatic peritoneal nodular thickening ( blue arrows ).

D . Axial PET / CT showing avid FDG uptake of the three hepatic focal lesions seen at segment VIII ( long red arrows ) and at segment VII ( short red arrow ) with peri hepatic peritoneal nodular thickening ( blue arrows ) previously noted on CECT , with a further FDG avid hepatic focal lesion seen at segment IV ( green arrow ) and two pancreatic lymphomatous focal lesions ( yellow arrows ), not seen on CECT .

primarily targeting CD20 and CD3 ( glofitamab , mosunetuzumab , epcoritamab , odronextamab ) are undergoing clinical trials in non-Hodgkin ’ s lymphomas with promising early results .

There are two key toxicities of bispecific agents : cytokine release syndrome and neurotoxicity . Cytokine release syndrome , characterised by fever , low blood pressure and hypoxia , is due to the release of inflammatory molecules in the process of T-cells killing cancer cells . Neurotoxicity , the mechanism of which is poorly understood , manifests as headache , tremor , confusion , difficulties with speech and , in severe cases , seizures .

Figure 5 . Bone marrow biopsy .

An elderly male presented with multiple enlarged nodes and no peripheral blood lymphocytosis . The primary diagnosis was made on an excisional biopsy of an inguinal node . This specimen is the marrow biopsy for staging .

CAR T-CELL THERAPY Chimeric antigen receptor ( CAR ) T-cell therapy is a new form of immunotherapy that involves removing T-cells from the patient and engineering them to be active against a particular target . 29 The T-cells are engineered with the gene to express a fragment of an antibody that is derived from a B-cell ( hence a ‘ chimera ’) that recognises an antigen on the target cancer cell . The gene is delivered to the T-cell with a viral vector .

CAR T-cells targeting CD19 on B-cells have proven efficacious in B acute lymphoblastic leukaemia and DLBCL , with patients having lasting remissions despite being refractory

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Zytoon AA , Mohamed HH , Mostafa BAAE , et al . PET / CT and contrast-enhanced CT : making a difference in assessment and staging of patients with lymphoma . Egypt J Radiol Nucl Med ; 51 , 213 ( 2020 )/ bit . ly / 3X5cHKF to chemotherapy . Because of the expense and resource intensiveness of CAR T-cell therapy , access is limited to designated centres and there is a national panel discussion process to guide approval of individual cases ( see box 2 ).

The process of autologous CAR T-cell production begins with collection of the patient ’ s lymphocytes ( apheresis ). As these are proprietary products , the manufacturing frequently occurs overseas and takes generally 4-8 weeks . During this time , patients may require further treatment to keep their disease under control (‘ bridging therapy ’). 30

Patients then receive a brief

Box 2 . Current eligibility for CAR T-cell therapy in Australia

• Products : Tisagenlecleucel ( Kymriah ) and axicabtagene ciloleucel ( Yescarta ).

• Adults with DLBCL ( a type of non-Hodgkin ’ s lymphoma , see figure 11 ) that does not respond to , or has relapsed after , two or more systemic therapies .

• Children and young adults ( up to 25 years old ) with acute lymphoblastic leukaemia that does not respond to standard treatment , in relapse posttransplant , or in second or later relapse .

course of chemotherapy designed to reduce their residual lymphoid cells (‘ lymphodepletion ’) before the CAR T-cells are infused . The main toxicities are cytokine release syndrome and neurotoxicity . Management of these issues has improved with experience , and includes the use of tocilizumab , a monoclonal antibody which blocks the interleukin 6 receptor and dampens the inflammatory milieu , and corticosteroids . Other complications can include low blood counts , infection and long-term need for immunoglobulin replacement . 31

CAR T-cells are being trialled earlier in patients ’ courses of treatment when T-cells may potentially be healthier , and in other disease groups such as multiple myeloma ( B-cell maturation antigen directed CAR T-cells ). 32

There remain barriers to the widespread availability of CAR T-cell therapy because of the logistics involved in production and delivery . Novel constructs that target more than one antigen , use of CAR T-cells earlier during treatment , and the development of allogeneic or ‘ off the shelf ’ products may overcome some of these hurdles .

Stem cell transplantation

There are two forms of bone marrow or haemopoietic stem cell transplantation — autologous and allogeneic . Autologous transplantation involves collecting blood stem cells through a peripheral line from the patient and reinfusing the cells after the patient has received a very high dose of chemotherapy . This delivery of higher doses of chemotherapy may be curative in a proportion of patients with lymphoma . 33

Allogeneic transplantation involves the infusion of stem cells from a donor and is a form of immunotherapy . Stem cell sources include peripheral blood , bone marrow and cord blood . Allogeneic transplantation is used as a treatment option for a small subset of patients with relapsed lymphoma , as it remains a procedure with considerable shortand long-term toxicity . Recent developments including the use of ‘ haplo-identical ’ ( half-matched ) donors , have broadened the range of candidates for transplantation . 34

Targeted small molecule therapies

The improved understanding of the biology of cancer has led to new therapeutic strategies that target mutations with specifically designed drugs . 35 This precise targeting of cancer cells contrasts with the broad cytotoxic approach of