Monoclonal Antibody (MoAb) Therapy in Non-Hodgkin’s Lymphomas

S. H. Lim, R. E. Marcus S UMMA R Y. The advance of monoclonal antibody (MoAb) technology in recent years provides a further treatment modality for cancer therapy. In this review, we discussed the various strategies available for MoAb therapy. We also addressed the problems encountered so far in early clinical trials and suggested possible solutions. We finally reviewed some of the interesting clinical studies conducted so far on the use of MoAbs in patients with non-Hodgkin’s lymphomas.

Despite the advance of modern chemotherapeutic regimens, the majority patients with non-Hodgkin’s lymphoma (NHL) still succumb to the disease. With an anthracycline-based combination chemotherapy regimen such as CHOP, complete remission (CR) rate in the region of 70% is obtained in intermediate/ high grade NHLle3 but many of these patients subsequently relapse of their disease. Attempts at increasing or alterating the chemotherapy regimens have however not produced any improvement in these results.4 Similarly, results of treatment of low grade NHL remain disappointing.5.6 Therefore other treatment modalities used either as a form of primary or adjuvant therapy are explored. Cancer immunotherapy attempts to influence the course of cancer in man by a variety of different immunological manoeuvres. This may be approached by modulating either the cellular cytotoxic, the humoral or both arms of the immune system. Clinical trials using non-specific immunostimulants such as BCG or specific T-cell stimulant such as interferons and interleukin-2 (IL-2) have produced mixed results7-’ and responses have been observed in some patients with refractory or relapsed diseases. The role of these agents in the adjuvant setting remains to be defined. Although tumour therapy with a specific antiS. H. Lim, R. E. Marcus, Department of Haematology, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. Correspondence to: Dr Seah H Lim Blood Reww~ (1992) 6, 157-162 ‘?I 1992 Longman Group UK Ltd

serum was first reported nearly 100 years ago, subsequent attempts at such approach were disappointing, due most probably to the lack of specificity and reproducibility of the animal sera. The discovery of the MoAb technology in the 1970s” and the genetic engineering of chimaeric or humanised monoclonal antibodies (MoAbs) in the 1980s” have, however, rekindled interest and optimism among oncologists of the potential role of MoAbs in cancer therapy. In this article, we will describe some of the ways in which MoAbs may be used for cancer therapy and the problems encountered so far in therapeutic trials. Some of the clinical trials involving the use of MoAbs in NHL will also be reviewed. Lastly, we will discuss the future directions for MoAb therapy in oncology. General Strategies

MoAbs may be used in a number of ways to treat malignant diseases. The first approach depends on the patient’s own immune system to clear the MoAbs coated malignant cells. Clearance of these cells may either be achieved by complement-mediated cytotoxicity or by antibody-dependent cellular cytotoxicity (ADCC). This approach therefore relies on the intrinsic properties of the MoAbs and the normal effector functions of the patients. A second approach is to use the MoAbs as a

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MOAB THERAPY IN NON-HODGKIN’S

LYMPHOMAS

delivery system (‘magic bullet’) to administer radiation, immunotoxin, cytotoxic drugs or biological response modifiers to the malignant cells. Here cytotoxicity occurs as a result of the direct action of these potentially cytotoxic substances on the malignant cells coated with the MoAbs. Such approach is theoretically attractive since it may avoid nonspecific toxicities. A third possibility is to use MoAbs for T-cell targetting of the malignant cells. This approach generally uses a bispecific antibody which has two different binding sites, one of which is capable of recognising tumour associated antigens on the one hand a lymphocyte epitope on the other. This process of cross-linking could result in the activation of the lymphocyte and triggering of its lytic cytotoxic machinery, as well as local lymphokine production. As a result, a cascade of tumour cytotoxic mechanisms may be generated locally. Here it is assumed that normal lymphocyte cytotoxic function is intact and the tumour cells are susceptible to such lytic action. The fourth approach is the targetting of the MoAbs to induce growth modulation. This can be achieved by a number of ways. MoAbs can be targetted against specific receptors on the cell surface which regulate growth of the neoplastic cells, examples of such receptors include IL-2 receptor, IL-6 receptors and epithelial grow factor (EGF) receptors. Hence signal transduction by the appropriate cytokine is blocked. Alternatively binding of the MoAbs may directly induce intracellular signals leading to apoptosis. Lastly, anti-idiotypic antibody may be used for active immunisation in cancer therapy (so-called antiidiotype vaccines). In this approach, the immunised patient responds by the production of anti-antiidiotype antibody which cross-react with the tumour antigen. Potential MoABs

Problems Associated

with the Use of

Whilst MoAbs are potentially more specific than conventional chemotherapy in their cytotoxic function, their use in tumour therapy is not without problems. These problems may be grouped into 3 categories depending on their origin: (1) Tumour factors; (2) Host factors, and (3) Antibody factors. Tumour Factors

Ideally the MoAbs chosen should be directed against an antigen which is tumour specific, abundantly expressed and present on all the target tumour cells (including the clonogenic cells) but absent on normal tissue, free from modulation, a good target for complement binding and not present in the plasma as soluble antigen. Unfortunately tumour specific antigens have thus far not been isolated in the majority of tumours. Most of the MoAbs used for therapeutic

purposes are at present tumour nonspecific, being also directed against either the normal counterpart of the tumour cells (e.g. Campath-l series, anti-CD25, anti-CD5)12-14 or the differentiation antigens (e.g. CD7, CD14/15, CDlO, CD33).15-18 Cells coated with the MoAbs, irrespective of whether they are normal or malignant, would therefore be cleared by the effector system, resulting in the nonspecificity of the MoAbs. Modulation of antigens results in the loss of antibody from the cell surface and prevents the natural host effector mechanism from clearance of the tumour cells. This occurs either as a result of capping, antigen shedding or endocytosis. Therefore therapeutic strategies for the use of such MoAbs need to be planned accordingly. The use of ‘naked’ MoAbs directed against an antigen which is modulated rapidly following binding will therefore invariably result in treatment failure. However, such property of the antigen can be exploited by the use of toxin-conjugated MoAbs whose cytotoxicity depends on the internalisation of the toxin. Antigen density on the tumour cell surface is a further potential problem; weakly expressed antigen will not be a good target for MoAbs therapy. This problem may sometimes be overcome by using synergistic pairs of antibodies, either against a different antigens or a different epitopes on the same antigens. The constant expression of the targetted antigen on the tumour cell surface is important for the success of MoAb therapy. One of the tumour escape mechanisms operating in tumour growth is the gradual loss and heterogeneity of the expression of the tumour antigenslg which will result in the gradual loss of efficacy of the MoAbs. This is generally not a major problem for MoAbs directed against a differentiation antigen but is seen frequently with the use of antiidiotype antibody.20 Such problem may hopefully be resolved by using radionuclide-conjugated MoAbs, the cytotoxic function of which relies on the effect of local radiation that may extend beyond the singlecell range. Host Factors

One of the main problem arising from the use of MoAbs is the immunogenicity of the MoAbs. This is especially so in the case of toxin-conjugated MoAbs. Since most MoAbs are murine-derived, patients treated with such MoAbs may develop an anti-globulin response. This typically occurs within lo-14 days following administration. Although theoretically the antiglobulin response may also aide in the clearance of any MoAbs bound tumours still present in the system, its neutralising property precludes further use. Patients may also develop antibody to the conjugated toxin. Clearance of the MoAb bound tumour cells relies largely on the interaction between the antibody and the Fc receptors on host effector cells. Since most

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MoAbs are murine-derived, such interaction may not be optimal. Clinical studies involving the use of either chimaeric or humanised MoAbs to alleviate this problem and the problem of immunogenicity are ongoing, although the immunogenicity of the MoAbs may not be a widespread problem in patients with lymphomas whose immune system is usually impaired, either as a result of the disease process or to prior cytotoxic drug therapy. The question of whether patients with lymphoma have normal effector functions needs to be addressed if use of ‘naked’ MoAbs is contemplated for the treatment of such patients. Although much work have shown that lymphoma patients exhibit various impairment in their T-cell functions, very little is presently known about their reticula-endothelial function.

Antibodv

Factors

Besides the intrinsic properties of the MoAbs, an important consideration for the successful use of antibody therapy is the accessibility of the tumour cells to the systemically administered MoAbs. Tumour penetration may be improved by the use of F(ab) fragments but such a manoeuvre may compromise the tumour cell clearance since the Fc fraction of the MoAbs is important for the regulation of ADCC and complement activation. Early indications from clinical trials suggest that patients with bone marrow and splenic diseases may respond better than those with solid tumours or nodal diseases.

Clinical

Trials

Therapy for relapsed refractory NHL is still unsatisfactory. Although ABMT may salvage some patients, many more patients die due to disease progression. It is therefore not surprising that efforts are made to seek other therapeutic options. To date, most of the clinical trials involving the use of MoAbs in NHL have been confined to phase I/II studies, determining primarily the feasibility and pharmacokinetics of a specific MoAb. Broadly, these trials can be analysed in two ways, firstly, the use of either ‘naked’ MoAbs or conjugated MoAbs; secondly, the use of MoAbs in the treatment of refractory relapsed NHL, in either the purging of autologous bone marrow prior to autologous bone marrow transplantation (ABMT) or more recently, as an adjuvant therapy post-ABMT for NHL.

MoAbs

in the Therap_v of Refractory/Relapsed

NHL

Native Unconjugated MoAbs. Patients with both B-cell and T-cell NHL have so far been treated with MoAbs. Brown et a12’ treated 16 patients with relapsed refractory B-NHL with rodent-derived anti-idiotype MoAbs and observed a CR of up to 6 years in 1 patient, partial responses (PR) in 7 and minor

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responses (MR) in 2. In this study patients were found to relapse with an increased number of idiotype-negative tumour cells, supporting the notion of tumour escape by the selection for idiotypenegative tumour cells. In the same study, 11 patients were treated with anti-idiotype MoAb in combination with IFN-a. 2 CRs, 7 PRs and 2 MRs were observed in this group. This result may be marginally better than that observed in patients receiving MoAbs alone, suggesting synergy between the MoAbs and the IFNa. However, this can only be confirmed in a larger patient population and ideally in the context of a randomised study. More recently, a panel of antishared idiotypic (SID) MoAbs have been developed and Miller et a122 used this panel of MoAbs to screen for reactivity in lymph node biopsies obtained from patients with relapsed NHL who were subsequently treated with the reactive anti-Id. So far 10 patients have been treated and tumour regression were observed in some patients with low grade NHL. The results however were disappointing in patients with high grade NHL. The Campath-l MoAb is an antibody which is reactive with the CD52 cluster of differentiation antigen expressed on the majority of lymphocytes and malignant lymphoid cells and some monocytes. The naked IgG MoAb has been used in a lo-day infusion schedule to treat 16 patients with relapsed NHL/ CLL.23 Of the 9 NHL patients treated, there were 2 PRs with a slight reduction in the lymphadenopathy in the other patients. In the two patients who attained PR, tumour regression was seen primarily in the blood, bone marrow and spleen but not lymph nodes. suggesting that the differential response may be due to the varying accessibility of the MoAbs to the tumour cells. Complimentarily determining regions (CDRs)-grafted humanised form of the Campath-l MoAb (Campath-1H) was subsequently used to treat two patients with relapsed NHL and both patients attained a durable period of CR without the development of human anti-rat antiglobulin response.24 A phase I/II multicentre feasibility and pharmacokinetic study involving various dose schedules of the use of Campath-IH MoAb is at present ongoing in patients with relapsed/refractory CLL and NHL. Another recent study of naked MoAb involved the use of mouse-derived anti-CD19 for patients with relapsed B-cell NHL. 25 In this study, 6 patients were treated with increasing doses of the MoAbs. Of these 6 patients, 1 PR and 1 MR were observed. The majority of T-cell NHL treated with MoAbs have been cutaneous T-cell lymphoma or mycosis fungoides. TlOl (anti-Leu-1) MoAb were used in two studies. In a phase I study,26 13 patients with T cell malignancies were treated (8 with cutaneous T-cell lymphoma) resulting in 1 CR and 1 PR. Another similar study reported on 4 patients treated with some tumour regression observed in 2 patients.” Knox et a12* administered chimaeric anti-CD4 to 7 multiply-treated patients with refractory mycosis

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fungoides (MF) in a dose escalation. Each patient in this study received 3 weeks of MoAb infusions. Although no depletion of the peripheral blood CD4 + lymphocytes occurred, 2 patients achieved PR, 1 MR and 3 patients stable disease (SD). MoAbs were only detected in the skin biopsies of patients receiving high doses of anti-CD4. In a similar study, we treated 2 patients with refractory MF, one with anti-CD4 and another with Campath-1G MoAbs (Lim et al, unpublished). Each patient received a total of 3 weeks of MoAb infusions and with gradual dose escalations. Serial skin biopsies were performed prior to and after infusions. There was no depletion of the peripheral blood CD4 + cells in the patient receiving anti-CD4 MoAb but profound panlymphopenia developed in the patient treated with Campath 1G MoAb. Skin biopsies in both patients failed to detect any MoAb and both patients did not show any significant clinical response to the therapy, suggesting again that MoAb inaccessibility to the tumour cells may be a major impediment to the success of MoAb therapy. Cutaneous T-cell lymphoma has also been approached by active immunisation with antiidiotypic vaccine.29 A phase I study is presently ongoing. In vitro work showed cross-reactivity of the anti-anti-idiotype antibody, developed as a result of the immunisation, with the tumour cells. 1 patient who has been treated so far achieved a durable SD. Conjugated MoAbs. The majority of studies have involved either MoAbs conjugated to 1311or to ricin. A phase I study of increasing doses of 1311-labelled OKB7 is being carried out in patients with relapsed B-cell NHL.30 OKB7 is a rodent-derived IgG2b which is reactive with gp140 expressed on B-cells and B-malignant cells. One third of patients treated with a total dose of 90 mCi and one third of patients treated with 120 mCi attained PR while 4/6 patients receiving 160 mCi showed tumour regression. Press et a131 used a combination of MB1 (antiCD37), Bl and IF5 (anti-CD20) conjugated to 1311 to treat patients with advanced refractory NHL. In this study, all prospective candidates received a test dose of MoAb in a preliminary MoAb localisation and distribution study. Only patients showing favourable MoAb localisation then received doses of radiation ranging from 233-628 mCi. 15 patients were treated and with a maximum follow-up period of 38 months, 12 patients achieved CR, 1 PR and 1 MR. Due to the bone marrow toxicity, autologous bone marrow rescue was used to restore haemopoiesis in the majority of patients given higher doses of radiation. Grossbard et a132 used toxin-conjugated MoAbs for patients with refractory NHL. Using B4 (anti CD19)-blocked ricin in a phase I study, 25 patients with B-cell NHL were treated with increasing doses of the MoAb for 5 days. 2 CRs and 5 PRs were observed in this cohort of patients. In another 8

patients, a mixed/transient response was attained. However, most of the responding patients were those with low-grade NHL/CLL. Overall, the main adverse reactions experienced by these patients in these studies were fever, rigor and hypotension. An incidence of around 30% of human anti-mouse or anti-rat antiglobulin response were observed. This is lower than that in patients with other diagnosis treated with rodent-derived MoAbs probably as a result of the already immunocompromised state, due to the disease process and/or previous intensive chemoradiotherapy. Besides the above mentioned adverse reactions, bone marrow toxicity is seen in patients treated with i311-labelled MoAbs. This limits dose escalation although the problem may be overcome either by autologous bone marrow rescue or the use of haemopoietic growth factors. MoAbs used in ex-vivo Bone Marrow Purging for ABMT

The main problem associated with ABMT is disease relapse either due to failure to eradicate the disease by the conditioning regimen or to reinfusion of contaminated bone marrow. Although ABMT is in general only carried out in patients without any obvious bone marrow disease, using the polymerasechain reaction (PCR), Gribben et a133 has demonstrated the presence of the bcl-2/IgH hybrid gene in nearly half of the patients with follicular NHL. Such results suggest the prevalence of bone marrow disease despite negative histology and also the presence of clonogenic tumour cells in the bone marrow which may not be distinguished microscopically from normal cells. Moreover, there was also a disease-free survival advantage in those patients whose re-infused bone marrow was negative for the bcl-2 hybrid gene as detected by PCR using both the primers for the major and minor breakpoint regions. Hence the rationale for the use of MoAbs to purge bone marrow prior to reinfusion to rid of any minimal residual disease is strong. Unfortunately, there is at present no randomised prospective trials comparing purging of autologous bone marrow with unmanipulated bone marrow in ABMT for NHL to confirm this. One of the earliest study demonstrating the feasibility of MoAb ex-vivo purging of autologous bone marrow in NHL involved the use of Bl (anti-CD20) MoAb.j4 In this study, 8 patients were treated and 6 patients remain in CR with a median follow-up period of 20 months. A similar study involved the use of a combination of Bl (anti-CD20) MoAb and B5 (an IgM MoAb directed against activated B cells) and J5 (anti-CDlO) was later reported.33 This showed the advantage of purging in patients whose re-infused bone marrow subsequently became bcl-2 negative. However, a smaller study but without any molecular analysis of the purged bone marrow failed to indicate any advantage of bone marrow purging.35

BLOOD REVIEWS

In this study, the bone marrows of 41 patients with B-lineage NHL were purged ex vivo with a cocktail of anti-CD19, anti-CD10 and anti-CD24 in combination with complement and the bone marrows of 12 patients with T-lineage NHL were treated ex-vivo with a combination of ricin-conjugated anti-CD5 and anti-CD7 together with 4-hydroperoxycyclophosphamide (4-HC). All patients had progressive NHL and were conditioned with cyclophosphamide and total body irradiation. There was no difference in the disease-free survival of this group of patients compared to a historical group who did not receive MoAb purged bone marrow. MoAhs as an Adjuvant Therapy Following ABMT The use of MoAbs following ABMT to eradicate any minimal residual disease and prolong disease-free survival is a new concept in MoAb therapy. Early the use of immunotoxinresults36 involving conjugated B4 (anti-CD19) as a 7-day infusion following ABMT for relapsed NHL is encouraging. In this study 12 patients were treated following ABMT and all 12 patients have remained in CR with a followup period of 4-18 months. All 8 patients whose bone marrow were positive by PCR for the bcl-2 major breakpoint region at the time of ABMT became negative following ABMT. This result is interesting but remains to be confirmed by larger randomised studies. Future Directions

Mod$cation

qf the MoAbs

One of the most promising new avenues is the development of bispecific anti-idiotype/antiCD3 antibody. Such MoAb binds to both CD3 and a tumourassociated antigen and induces T-cell lysis of the target cells irrespective of the TCR-specificity. Bispecific MoAbs have been used in murine models37,38 of B-cell lymphomas. Early results indicated that they are effective in both the prevention of inoculated lymphoma cells and the eradication of established tumours. They may also be less toxic and more superior to anti-ld, anti-CD3 or a combination of the two MoAbs. Efficacy of the cytotoxic function of MoAbs may also be improved by the genetic engineering of monovalent MoAbs. One of the main problems of MoAb therapy in solid tumours is the accessibility of the MoAbs to the tumour cells. By virtue of its smaller physical size, monovalent MoAbs may overcome this problem. Moreover, in vitro work involving the design of monovalent CD339 indicated that the complement-mediated lysis may also be enhanced. Improvement of the &,Sector Functions Independent of the affinity or the intrinsic property of the MoAbs, one of the most important factor

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determining the success of MoAb in tumour therapy is the presence of an intact system of effector functions. In this respect, ADCC is probably most important. Various in-vitro studies have indicated that the ADCC may be upregulated by various cytokines, such as Interferon-y, IL-2, IL-6, GM-CSF and TNF-a40-44. Hence it may be possible to enhance the in vivo efficacy of MoAb therapy by using the MoAb with the appropriate cytokines.

MoAbs in combination with Cytotoxic Chemotherapy One of the main problems leading to treatment failure of anti-idiotype MoAb therapy is the emergence or positive selection for tumour clones lacking the expression of the tumour-associated antigen. It may however be possible to overcome this problem with the addition of a cytotoxic chemotherapy. Such combination immunochemotherapy may improve tumour therapy.

Conclusions

A series of questions remains to be answered regarding the improvement in clinical response rates following MoAb therapy. They include the types and doses of MoAbs to be used and whether or not such MoAbs should be used naked or conjugated to immunotoxin, cytotoxic drugs or radionuclides. Much debate has also been focussed on the types of radionuclide to use for this purpose. But most important, we still need to define the best clinical setting when MoAbs would be most effective. However, we ought not to be overexcited by early successes or dampened by subsequent failures and problems relating to its use. Instead, these efforts should provide the foundation for further development of innovative strategies for cancer immunotherapy.

Acknowledgement SHL is funded by the Leukaemia Research Fund (LRF) research fellowship.

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Monoclonal antibody (MoAb) therapy in non-Hodgkin's lymphomas.

The advance of monoclonal antibody (MoAb) technology in recent years provides a further treatment modality for cancer therapy. In this review, we disc...
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